U.S. patent application number 16/958057 was filed with the patent office on 2021-03-04 for anticancer agent.
This patent application is currently assigned to JAPANESE FOUNDATION FOR CANCER RESEARCH. The applicant listed for this patent is JAPANESE FOUNDATION FOR CANCER RESEARCH, KABUSHIKI KAISHA YAKULT HONSHA, RIKEN. Invention is credited to Yukiko MURAMATSU, Hiroyuki SEIMIYA, Fumiyuki SHIRAI, Kenichi WASHIZUKA, Yoko YASHIRODA, Minoru YOSHIDA.
Application Number | 20210060016 16/958057 |
Document ID | / |
Family ID | 1000005249712 |
Filed Date | 2021-03-04 |
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United States Patent
Application |
20210060016 |
Kind Code |
A1 |
SEIMIYA; Hiroyuki ; et
al. |
March 4, 2021 |
ANTICANCER AGENT
Abstract
To provide an anticancer agent for preventing and/or treating
cancer, comprising a tankyrase inhibitor containing a tankyrase
inhibitory compound and a microtubule inhibitor containing a
microtubule inhibitory compound as active ingredients.
Inventors: |
SEIMIYA; Hiroyuki; (Koto-ku,
JP) ; YOSHIDA; Minoru; (Wako-shi, JP) ;
YASHIRODA; Yoko; (Wako-shi, JP) ; MURAMATSU;
Yukiko; (Koto-ku, JP) ; SHIRAI; Fumiyuki;
(Wako-shi, JP) ; WASHIZUKA; Kenichi; (Wako-shi,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JAPANESE FOUNDATION FOR CANCER RESEARCH
RIKEN
KABUSHIKI KAISHA YAKULT HONSHA |
Koto-ku
Wako-shi
Minato-ku |
|
JP
JP
JP |
|
|
Assignee: |
JAPANESE FOUNDATION FOR CANCER
RESEARCH
Koto-ku
JP
RIKEN
Wako-shi
JP
KABUSHIKI KAISHA YAKULT HONSHA
Minato-ku
JP
|
Family ID: |
1000005249712 |
Appl. No.: |
16/958057 |
Filed: |
December 26, 2018 |
PCT Filed: |
December 26, 2018 |
PCT NO: |
PCT/JP2018/047937 |
371 Date: |
June 25, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 35/00 20180101; A61K 31/517 20130101; A61K 31/337 20130101;
A61K 31/36 20130101; A61K 31/513 20130101; A61K 31/519 20130101;
A61K 31/475 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/337 20060101 A61K031/337; A61K 31/475 20060101
A61K031/475; A61K 31/36 20060101 A61K031/36; A61K 45/06 20060101
A61K045/06; A61P 35/00 20060101 A61P035/00; A61K 31/513 20060101
A61K031/513; A61K 31/517 20060101 A61K031/517 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 2017 |
JP |
2017-252178 |
Claims
1. A method for treating a cancer, comprising administering to a
subject in need thereof a tankyrase inhibitor and a microtubule
inhibitor as active ingredients.
2-4. (canceled)
5. The method according to claim 1, wherein the tankyrase
inhibitory compound acts on at least one of a nicotinamide binding
pocket of tankyrase and an adenosine binding pocket of
tankyrase.
6. The method according to claim 1, wherein the tankyrase
inhibitory compound is at least one compound selected from the
group consisting of a compound of formula (1), a compound of
formula (11), and a salt thereof, wherein the compound of formula
(1) is: ##STR00060## wherein A.sup.1, A.sup.2, A.sup.3, and A.sup.4
form a structure in which A.sup.1 and A.sup.2 each represent a
single bond, one of A.sup.1 and A.sup.2 represents a single bond
and the other represents CH.sub.2, or A.sup.1 represents a single
bond and A.sup.4 represents CH.sub.2, with the proviso that one of
A.sup.3 and A.sup.4 is CH.sub.2 or CO and the other is O or NR when
A.sup.1 and A.sup.2 each represent a single bond or A.sup.1
represents CH.sub.2 and A.sup.2 represents a single bond, one of
A.sup.3 and A.sup.4 is NR.sup.1 and the other is CH.sub.2 or CO
when A.sup.1 represents a single bond and A.sup.2 represents
CH.sub.2, and one of A.sup.2 and A.sup.3 is NR.sup.1 and the other
is CH.sub.2 or CO when A.sup.1 represents a single bond and A.sup.4
represents CH.sub.2, where R.sup.1 represents a hydrogen atom, an
optionally substituted C.sub.1-6 alkyl group, an optionally
substituted heteroaryl group, an optionally substituted C.sub.3-8
cycloalkyl C.sub.1-3 alkyl group, an optionally substituted aryl
C.sub.1-3 alkyl group, an optionally substituted heteroaryl
C.sub.1-3 alkyl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl C.sub.1-3 alkyl group, a group
represented by the formula: --(CH.sub.2).sub.m--C(.dbd.O)-L, or a
group represented by the formula: --S(.dbd.O).sub.2--R.sup.13, m is
0, 1, 2, or 3, wherein L is R.sup.11 when m is 0, and wherein L is
R.sup.12 when m is 1, 2, or 3, R.sup.11 is a hydrogen atom, an
optionally substituted C.sub.1-6 alkyl group, OR.sup.51, a group
represented by the formula: --C(.dbd.O)--OR.sup.52, or a group
represented by the formula: --N(R.sup.53a)--R.sup.53b, R.sup.51 is
an optionally substituted aryl C.sub.1-3 alkyl group, R.sup.52 is a
hydrogen atom or an optionally substituted C.sub.1-6 alkyl group,
R.sup.53a and R.sup.53b are each independently a hydrogen atom or
an optionally substituted C.sub.1-6 alkyl group, or R.sup.53a and
R.sup.53b are linked together to form a three- to seven-membered
ring heterocycloalkyl group optionally comprising at least one atom
or group selected from the group consisting of an oxygen atom, a
sulfur atoms and NR.sup.81, R.sup.81 is a hydrogen atom or an
optionally substituted C.sub.1-6 alkyl group, R.sup.12 is an
optionally substituted aryl group, OR.sup.54, or a group
represented by the formula: --N(R.sup.55a)--R.sup.55b, R.sup.54 is
a hydrogen atom, an optionally substituted C.sub.1-6 alkyl group,
an optionally substituted aryl C.sub.1-3 alkyl group, or an
optionally substituted heteroaryl C.sub.1-3 alkyl group, R.sup.55a
and R.sup.55b are each independently a hydrogen atom, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted aryl
C.sub.1-3 alkyl group, an optionally substituted heteroaryl
C.sub.1-3 alkyl group, or a group represented by the formula:
--(C.dbd.O)--R.sup.82, or R.sup.55a and R.sup.55b are linked
together to form a three- to seven-membered ring heterocycloalkyl
group optionally comprising at least one atom or group selected
from the group consisting of an oxygen atom, a sulfur atom, and
NR.sup.83, or R.sup.55a and R.sup.55b are linked together to form
an optionally substituted
6,8-dihydro-5H-imidazolo[1,2-a]pyrazin-7-yl group, R.sup.82 is a
hydrogen atom, an optionally substituted C.sub.1-6 alkyl group, or
an optionally substituted aryl C.sub.1-3 alkyl group, R.sup.83 is a
hydrogen atom or an optionally substituted C.sub.1-6 alkyl group,
and R.sup.13 is an optionally substituted C.sub.1-6 alkyl group;
the structure formed by E.sup.1, E.sup.2, E.sup.3, and E.sup.4 is a
group represented by the formula: -E.sup.1-E.sup.2-E.sup.3-E.sup.4-
where the bonds between E.sup.1, E.sup.2, E.sup.3 and E.sup.4 are
each independently a single bond or a double bond, in which E.sup.1
is N or CR.sup.2, E.sup.2 is N or CR.sup.3, E.sup.3 is N or
CR.sup.4, and E.sup.4 is N or CR.sup.5, a group represented by the
formula: -E.sup.2-E.sup.3=E.sup.4- in which E.sup.2 is O or S, and
each of E.sup.3 and E.sup.4 is CH with E representing a single
bond, or a group represented by the formula:
-E.sup.2=E.sup.3-E.sup.4- in which each of E.sup.2 and E.sup.3 is
CH, and E.sup.4 is O or S with E.sup.1 representing a single bond,
where R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each independently
selected from the group consisting of a hydrogen atom, a fluorine
atom, a chlorine atom, a bromine atom, an iodine atom, a cyano
group, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl group, and a group represented
by the formula: -Q-(CH.sub.2).sub.n--R.sup.14, n is 0, 1, 2, or 3,
Q is a group represented by the formula: --CH.dbd.CH--, O, CO, a
group represented by the formula: --C(.dbd.O)--O--, a group
represented by the formula: --C(.dbd.O)--N(R.sup.56)--, NR.sup.56,
a group represented by the formula: --N(R.sup.56)--C(.dbd.O)--, or
a group represented by the formula: --N(R.sup.56)--C(.dbd.O)--O--,
R.sup.56 is a hydrogen atom, an optionally substituted C.sub.1-3
alkyl group, or a group represented by the formula:
--C(.dbd.O)--R.sup.84, R.sup.84 is a hydrogen atom, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted aryl
group, an optionally substituted C.sub.1-6 alkyloxy group, or an
optionally substituted aryloxy group, and R.sup.14 is a hydrogen
atom, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted C.sub.3-8 cycloalkyl
group, or an optionally substituted three- to seven-membered ring
heterocycloalkyl group; and the structure formed by G.sup.1,
G.sup.2, G.sup.3, and G.sup.4 is a group represented by the
formula: -G.sup.1-G.sup.2-G.sup.3-G.sup.4-, wherein the bonds
between G.sup.1, G.sup.2, G.sup.3, and G.sup.4 are each
independently single bonds or double bonds, wherein the group is
represented by the formula: --CH.dbd.CH--CH.dbd.CR.sup.6-- (with
the exception of cases where A.sup.1 and A.sup.2 each represent a
single bond, with A.sup.3 being O and A.sup.4 being CO), the
formula: --CH.dbd.CH--CH.dbd.N-- (with the exception of cases where
A.sup.1 and A.sup.2 each represent a single bond, with A.sup.3
being O and A.sup.4 being CO), the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CO--CH.sub.2--CH.sub.2--N(R.sup.7)--, the formula:
--CH.sub.2--CF.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--O--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--S--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--N(R.sup.7)--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--O--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--N(R.sup.7)-- or the formula:
--O--CH.sub.2--CH.sub.2--N(R.sup.7)--, or a group represented by
the formula: -G.sup.2-G.sup.3-G.sup.4- wherein the bonds between
G.sup.2, G.sup.3, and G.sup.4 are each independently single bonds
or double bonds, wherein G.sup.1 represents a single bond, wherein
the group is represented by the formula: --CH.dbd.CH--N(R.sup.7)--,
the formula: --CH.sub.2--CH.sub.2--N(R.sup.7)--, the formula:
--N.dbd.CH--N(R.sup.7)--, or the formula: --N(R.sup.7)--CH.dbd.N--,
where R.sup.6 is a hydrogen atom, a fluorine atom, a chlorine atom,
a bromine atom, an iodine atom, an optionally substituted C.sub.1-6
alkyl group, or an optionally substituted C.sub.1-6 alkyloxy group,
R.sup.7 is a hydrogen atom, an optionally substituted C.sub.1-6
alkyl group, an optionally substituted C.sub.3-8 cycloalkyl group,
an optionally substituted C.sub.3-8 cycloalkyl C.sub.1-3 alkyl
group, an optionally substituted three- to seven-membered ring
heterocycloalkyl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl C.sub.1-3 alkyl group, a group
represented by the formula:--C(.dbd.O)--R.sup.15, or a group
represented by the formula
--(CH.sub.2).sub.p--C(.dbd.O)--OR.sup.16, p is 0, 1, 2, or 3,
R.sup.15 is a hydrogen atom, an optionally substituted C.sub.1-6
alkyl group, or OR.sup.57, R.sup.57 is an optionally substituted
C.sub.1-6 alkyl group or an optionally substituted aryl C.sub.1-3
alkyl group, and R.sup.16 is a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group; wherein the compound of the
formula (11) is: ##STR00061## wherein J.sub.1 and J.sub.2 each
represent CH or N, with the proviso that both J.sub.1 and J.sub.2
do not represent CH; r represents 0 to 4; each R.sup.101 is the
same or different when r is 2 or more, and each R.sup.1-1
represents a halogen atom, a C.sub.1-6 alkyl group optionally
substituted with a halogen atom, OR.sup.111, or a group represented
by the formula: --N(R.sup.112a)--R.sup.112b, where R.sup.111,
R.sup.112a, and R.sup.112b are each independently a hydrogen atom
or a C.sub.1-6 alkyl group, and s represents 0 to 5; each R.sup.102
is the same or different when s is 2 or more, and each R.sup.102
represents a halogen atom, a C.sub.1-6 alkyl group, OR.sup.113, a
group represented by the formula: --N(R.sup.114a)--R.sup.114b, a
group represented by the formula: --NH--C(.dbd.O)--R.sup.115, a
group represented by the formula: --C(.dbd.O)--R.sup.116, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, a nitro group, or a cyano group, where R.sup.113
is a hydrogen atom, an optionally substituted alkyl group, an
optionally substituted aryl group, an optionally substituted
arylalkyl group, or an optionally substituted heteroaryl group,
R.sup.114a and R.sup.114b are each independently a hydrogen atom or
a C.sub.1-6 alkyl group, R.sup.115 is an optionally substituted
alkyl group, an optionally substituted aryl group, an optionally
substituted heteroaryl group, or a group represented by the
formula: --NH--R.sup.121, R.sup.116 is an optionally substituted
alkyl group, an optionally substituted aryl group, an optionally
substituted heteroaryl group, OR.sup.122, or a group represented by
the formula: --N(R.sup.123a)--R.sup.123b, R.sup.121 is an
optionally substituted alkyl group, an optionally substituted aryl
group, or an optionally substituted heteroaryl group, R.sup.122 is
a hydrogen atom, an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group, and R.sup.123a and R.sup.123b are each
independently a hydrogen atom, an optionally substituted alkyl
group, an optionally substituted aryl group, or an optionally
substituted heteroaryl group, or R.sup.123a and R.sup.123b are
linked together to form a cyclic amine; R.sup.103 represents a
hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.3-6 cycloalkyl
group, or a C.sub.3-6 cycloalkyl C.sub.1-6 alkyl group; and
R.sup.101 and R.sup.103 are optionally linked together to form a
five- to seven-membered hetero ring when R.sup.101 is present at
the 8-position.
7. The method according to claim 1, wherein the microtubule
inhibitory compound is at least one compound selected from the
group consisting of paclitaxel, vinblastine, vincristine,
vindesine, vinorelbine, docetaxel, cabazitaxel, eribulin, and a
pharmacologically acceptable salt thereof.
8. The method according to claim 1, wherein the cancer is
colorectal cancer.
9. (canceled)
10. The method according to claim 1, further comprising
administering to the subject at least one agent selected from the
group consisting of an alkylating agent, an antimetabolite, a plant
alkaloid, a topoisomerase inhibitor, an anticancer antibiotic
substance, and a platinating agent.
11. The method according to claim 6, wherein the tankyrase
inhibitory compound is the compound of formula (1) or a salt
thereof.
12. The method according to claim 6, wherein the tankyrase
inhibitory compound is the compound of formula (11) or a salt
thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to an anticancer agent and a
kit for preventing and/or treating a cancer.
BACKGROUND ART
[0002] Poly(ADP-ribosyl)ation is a biochemical reaction which is a
chain addition of ADP-ribose to glutamic acid or aspartic acid
residues of a protein, with nicotinamide adenine dinucleotide as a
substrate. A produced poly(ADP-ribose) chain is composed of about
200 ADP-riboses at longest. A poly(ADP-ribose) polymerase (PARP)
family is known as an enzyme which catalyzes the
poly(ADP-ribosyl)ation reaction.
[0003] Of the PARP family, PARP-5a and PARP-5b are called
tankyrase-1 and tankyrase-2, respectively. Normally, in many cases,
both enzymes are simply called tankyrase collectively. The
tankyrase is composed of an ankyrin region which recognizes a
protein which is to be poly(ADP-ribosyl)ated; a sterile alpha motif
(SAM) region which is involved in self-multimerization; and a PARP
catalytic domain which controls the poly(ADP-ribosyl)ation
reaction.
[0004] The tankyrase binds to various proteins through the ankyrin
region in the molecule to poly(ADP-ribosyl)ate these proteins.
Examples of tankyrase-bound proteins include TRF1, NuMA, Plk1,
Miki, Axin, TNKS1BP1, IRAP, Mcl-1 and 3BP2. The tankyrase
poly(ADP-ribosyl)ates these proteins to regulate the physiological
functions of the proteins. Hence, inhibition of tankyrase is
considered to be effective for the control of cell proliferation,
cell differentiation, tissue formation and the like which are the
physiological functions of the proteins.
[0005] Examples of known tankyrase inhibitory compounds having
tankyrase inhibitory activity include the compound XAV939 described
in Non Patent Literature 1 (Huang SM. et al., Nature, Vol. 461, pp.
614-620, 2009), the compounds described in Patent Literature 1 (WO
2013/117288) and Patent Literature 2 (WO 2013/182580), NVP-TNKS656
described in Non Patent Literature 2 (Michael D. Shultz et al.,
Journal of Medicinal Chemistry, 56, pp. 6495-6511, 2013), and
G007-LK described in Non Patent Literature 3 (Andrew Voronkov. et
al., Journal of Medicinal Chemistry, 56, pp. 3012-3023, 2013) and
Patent Literature 3 (WO 2012/076898).
[0006] A microtubule is a protein forming a cytoskeleton, and is
involved in formation of a spindle in the phase of cell division
period, formation and maintenance of cellular morphology,
arrangement of intracellular organelles and transport of substances
to the organs, axonal transport in nerve cells, and the like. The
microtubule is composed of tubulin dimers each composed of an
.alpha.-subunit and a .beta.-subunit. A process in which the dimers
aggregate to form a microtubule is referred to as polymerization,
and a process in which a microtubule reverts to a tubulin is
referred to as depolymerization.
[0007] As microtubule inhibitors which inhibit microtubules,
microtubule depolymerization inhibitors for promoting the
polymerization to stabilize and excessively form microtubules, and
microtubule polymerization inhibitors for inhibiting the
polymerization are known, and these microtubule inhibitors each
suppress cell proliferation by disrupting the state of dynamic
equilibrium of microtubule polymerization to arrest the cell cycle
in the M phase. As such microtubule inhibitors, paclitaxel,
vinblastine, vincristine, vindesine, vinorelbine, docetaxel,
cabazitaxel, eribulin and the like are known. These microtubule
inhibitors are commercially available as agents having an antitumor
effect on leukemia, malignant lymphoma and malignant tumors.
[0008] Such tankyrase inhibitors and microtubule inhibitors are
considered to have an effect against fibrosarcoma, ovary cancer,
glioblastoma, pancreatic cancer, breast cancer, astrocytoma, lung
cancer, gastric cancer, hepatocyte cancer, multiple myeloma,
colorectal intestine cancer, bladder cancer, leukemia, infections
with a Herpes simplex virus, an Epstein-Barr virus and the like,
fibroses such as pulmonary fibrosis, cherubism, multiple sclerosis,
amyotrophic lateral sclerosis, skin and cartilage injuries,
metabolic diseases and the like, and a suppressive effect on cancer
metastasis. Development of a new pharmaceutical product (anticancer
agent) for preventing and/or treating the above-mentioned diseases,
particularly proliferative diseases such as a cancer, is
desired.
[0009] For example, Non Patent Literature 4 (Oriol Arques et al.,
Clinical Cancer Research, 22 (3), pp. 644-656, 2016), Non Patent
Literature 5 (Kevin S. Quackenbush et al., Oncotarget, Vol. 7, No.
19, pp. 28273-28285, 2016) and Non Patent Literature 6 (Hannah A.
Scarborough et al., Clinical Cancer Research, 23 (6), pp.
1531-1541, 2017) disclose use of a tankyrase inhibitory compound
along with an inhibitor against PI3 kinase or AKT which is a
survival signal kinase (Non Patent Literature 4), irinotecan which
is a topoisomerase inhibitor (Non Patent Literature 5) and EGFR
tyrosine kinase inhibitor (Non Patent Literature 6).
CITATION LIST
Patent Literature
[0010] Patent Literature 1: WO 2013/117288 [0011] Patent Literature
2: WO 2013/182580 [0012] Patent Literature 3: WO 2012/076898
Non Patent Literature
[0012] [0013] Non Patent Literature 1: Huang SM. et al., Nature,
Vol. 461, pp. 614-620, 2009 [0014] Non Patent Literature 2: Michael
D. Shultz et al., Journal of Medicinal Chemistry, 56, pp.
6495-6511, 2013 [0015] Non Patent Literature 3: Andrew Voronkov. et
al., Journal of Medicinal Chemistry, 56, pp. 3012-3023, 2013 [0016]
Non Patent Literature 4: Oriol Arques et al., Clinical Cancer
Research, 22 (3), pp. 644-656, 2016 [0017] Non Patent Literature 5:
Kevin S. Quackenbush et al., Oncotarget, Vol. 7, No. 19, pp.
28273-28285, 2016 [0018] Non Patent Literature 6: Hannah A.
Scarborough et al., Clinical Cancer Research, 23 (6), pp.
1531-1541, 2017
Problem to Solve
[0019] The present invention was made in view of the above problems
of the conventional technology. The present invention aims to
provide an anticancer agent and a kit, useful for treating and/or
preventing proliferative diseases such as a cancer.
Solution
[0020] The present inventors earnestly studied to solve the above
problems and found that use of a combination of a tankyrase
inhibitory compound and a microtubule inhibitory compound is useful
for treating and/or preventing proliferative diseases such as a
cancer, thereby completed the present invention.
[0021] That is, the present invention encompasses the
following:
[1] An anticancer agent for preventing and/or treating a cancer,
comprising a combination of a tankyrase inhibitor containing a
tankyrase inhibitory compound as an active ingredient and a
microtubule inhibitor containing a microtubule inhibitory compound
as an active ingredient. [2] An anticancer agent for preventing
and/or treating a cancer, which is used to be administered in
combination with a microtubule inhibitor containing a microtubule
inhibitory compound as an active ingredient and which contains a
tankyrase inhibitory compound as an active ingredient. [3] An
anticancer agent for preventing and/or treating a cancer, which is
used to be administered in combination with a tankyrase inhibitor
containing a tankyrase inhibitory compound as an active ingredient
and which contains a microtubule inhibitory compound as an active
ingredient. [4] An anticancer agent for preventing and/or treating
a cancer, comprising a tankyrase inhibitory compound and a
microtubule inhibitory compound as active ingredients. [5] The
anticancer agent according to any one of claims 1 to 4, where the
tankyrase inhibitory compound acts on at least one of a
nicotinamide binding pocket of tankyrase and an adenosine binding
pocket of tankyrase. [6] The anticancer agent according to any one
of claims 1 to 5, where the tankyrase inhibitory compound is at
least one compound selected from the group consisting of:
[0022] a compound of the formula (1):
##STR00001##
[0023] where A.sup.1, A.sup.2, A.sup.3 and A.sup.4 form a structure
in which A.sup.1 and A.sup.2 each represent a single bond, one of A
and A.sup.2 represents a single bond and the other represents
CH.sub.2, or A.sup.1 represents a single bond and A.sup.4
represents CH.sub.2,
[0024] with the proviso that one of A.sup.1 and A.sup.4 is CH.sub.2
or CO and the other is O or NR.sup.1 when A.sup.1 and A.sup.2 each
represent a single bond or A.sup.1 represents CH.sub.2 and A.sup.2
represents a single bond, one of A.sup.3 and A.sup.4 is NR.sup.1
and the other is CH; or CC when A.sup.1 represents a single bond
and A.sup.2 represents CH.sub.2, and one of A.sup.2 and A.sup.3 is
NR.sup.1 and the other is CH.sub.2 or CO when A.sup.1 represents a
single bond and A.sup.4 represents CH.sub.2,
[0025] where R.sup.1 represents a hydrogen atom, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
heteroaryl group, an optionally substituted C.sub.3-8 cycloalkyl
C.sub.1-3 alkyl group, an optionally substituted aryl C.sub.1-3
alkyl group, an optionally substituted heteroaryl C.sub.1-3 alkyl
group, an optionally substituted three- to seven-membered ring
heterocycloalkyl C.sub.1-3 alkyl group, a group represented by the
formula: --(CH.sub.2).sub.m--C(.dbd.O)-L, or a group represented by
the formula: --S(.dbd.O).sub.2--R.sup.13,
[0026] m is 0, 1, 2 or 3, L is R.sup.11 when m is 0, and L is
R.sup.12 when m is 1, 2 or 3,
[0027] R.sup.11 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, OR.sup.51, a group represented by the
formula: --C(.dbd.O)--OR.sup.52, or a group represented by the
formula: --N(R.sup.53a)--R.sup.53b,
[0028] R.sup.51 is an optionally substituted aryl C.sub.1-3 alkyl
group,
[0029] R.sup.52 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group,
[0030] R.sup.53a and R.sup.53b are each independently a hydrogen
atom or an optionally substituted C.sub.1-6 alkyl group, or
R.sup.53a and R.sup.53b are linked together to form a three- to
seven-membered ring heterocycloalkyl group optionally containing at
least one atom or group selected from the group consisting of an
oxygen atom, a sulfur atom and NR.sup.81,
[0031] R.sup.81 is a hydrogen atom or an optionally substituted
C.sub.1--, alkyl group,
[0032] R.sup.12 is an optionally substituted aryl group, OR.sup.54,
or a group represented by the formula:
--N(R.sup.55a)--R.sup.55b,
[0033] R.sup.54 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted aryl C.sub.1-3
alkyl group, or an optionally substituted heteroaryl C.sub.1-3
alkyl group,
[0034] R.sup.55a and R.sup.55b are each independently a hydrogen
atom, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted aryl C.sub.1-3 alkyl group, an optionally
substituted heteroaryl C.sub.1-3 alkyl group, or a group
represented by the formula: --(C.dbd.O)--R.sup.82, or R.sup.55a and
R.sup.55b are linked together to form a three- to seven-membered
ring heterocycloalkyl group optionally containing at least one atom
or group selected from the group consisting of an oxygen atom, a
sulfur atom and NR.sup.83, or form an optionally substituted
6,8-dihydro-5H-imidazolo[1,2-a]pyrazin-7-yl group,
[0035] R.sup.82 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, or an optionally substituted aryl C.sub.1-3
alkyl group,
[0036] R.sup.83 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group, and
[0037] R.sup.13 is an optionally substituted C.sub.1-6 alkyl
group;
[0038] the structure formed by E.sup.1, E.sup.2, E.sup.3 and
E.sup.4 is a group represented by the formula:
-E.sup.1-E.sup.2-E.sup.3-E.sup.4- (where the bonds between E.sup.1,
E.sup.2, E.sup.3 and E.sup.4 are single bonds or double bonds) in
which E.sup.1 is N or CR.sup.2, E.sup.2 is N or CR.sup.3, E.sup.3
is N or CR.sup.4 and E.sup.4 is N or CR.sup.5, a group represented
by the formula: -E.sup.2-E.sup.3=E.sup.4- in which E.sup.2 is O or
S and each of E.sup.3 and E.sup.4 is CH with E.sup.1 representing a
single bond, or a group represented by the formula:
-E.sup.2=E.sup.3-E.sup.4- in which each of E.sup.2 and E.sup.3 is
CH and E.sup.4 is O or S with E representing a single bond,
[0039] where R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each
independently a hydrogen atom, a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom, a cyano group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted aryl
group, an optionally substituted heteroaryl group, an optionally
substituted three- to seven-membered ring heterocycloalkyl group,
or a group represented by the formula:
-Q-(CH.sub.2).sub.n--R.sup.14,
[0040] n is 0, 1, 2 or 3,
[0041] Q is a group represented by the formula: --CH.dbd.CH--, O,
CO, a group represented by the formula: --C(.dbd.O)--O--, a group
represented by the formula: --C(.dbd.O)--N(R.sup.56)--, NR.sup.56,
a group represented by the formula: --N(R.sup.5)--C(.dbd.O)--, or a
group represented by the formula:
--N(R.sup.56)--C(.dbd.O)--O--,
[0042] R.sup.56 is a hydrogen atom, an optionally substituted
C.sub.1-3 alkyl group, or a group represented by the formula:
--C(.dbd.O)--R.sup.84,
[0043] R.sup.84 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, or an optionally substituted aryl group, an
optionally substituted C.sub.1-6 alkyloxy group, or an optionally
substituted aryloxy group, and
[0044] R.sup.14 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally substituted
C.sub.3-8 cycloalkyl group, or an optionally substituted three- to
seven-membered ring heterocycloalkyl group; and
[0045] the structure formed by G.sup.1, G.sup.2, G.sup.3 and
G.sup.4 is a group represented by the formula:
-G.sup.1-G.sup.2-G.sup.3-G.sup.4- (where the bonds between G.sup.1,
G.sup.2, G.sup.3 and G.sup.4 are single bonds or double bonds)
which is represented by the formula: --CH.dbd.CH--CH.dbd.CR.sup.6--
(with the exception of cases where A.sup.1 and A.sup.2 each
represent a single bond, with A.sup.3 being O and A.sup.4 being
CO), the formula: --CH.dbd.CH--CH.dbd.N-- (with the exception of
cases where A.sup.1 and A.sup.2 each represent a single bond, with
A.sup.3 being O and A.sup.4 being CO), the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CO--CH.sub.2--CH.sub.2--N(R)--, the formula:
--CH.sub.2--CF.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--O--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--S--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--N(R.sup.7)--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--O--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--N(R')-- or the formula:
--O--CH.sub.2--CH.sub.2--N(R')--, or a group represented by the
formula: -G.sup.2-G.sup.3-G.sup.4- (where the bonds between
G.sup.2, G.sup.3 and G.sup.4 are single bonds or double bonds)
which is represented by the formula: --CH.dbd.CH--N(R.sup.7)--, the
formula: --CH.sub.2--CH.sub.2--N(R.sup.7)--, the formula:
--N.dbd.CH--N(R.sup.7)-- or the formula: --N(R.sup.7)--CH.dbd.N--,
with G.sup.1 representing a single bond,
[0046] where R.sup.6 is a hydrogen atom, a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom, an optionally
substituted C.sub.1-6 alkyl group, or an optionally substituted
C.sub.1-6 alkyloxy group,
[0047] R.sup.7 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.3-3
cycloalkyl group, an optionally substituted C.sub.3-8 cycloalkyl
C.sub.1-3 alkyl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl group, an optionally
substituted three- to seven-membered ring heterocycloalkyl
C.sub.1-3 alkyl group, a group represented by the
formula:--C(.dbd.O)--R.sup.15, or a group represented by the
formula --(CH.sub.2).sub.p--C(.dbd.O)--OR.sup.16,
[0048] p is 0, 1, 2 or 3,
[0049] R.sup.15 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group or OR.sup.57,
[0050] R.sup.57 is an optionally substituted C.sub.1-3 alkyl group,
or an optionally substituted aryl C.sub.1-3 alkyl group, and
[0051] R.sup.16 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group;
[0052] a compound of the formula (11):
##STR00002##
[0053] where J.sub.1 and J.sub.2 each represent CH or N, with the
proviso that both J.sub.1 and J.sub.2 do not represent CH;
[0054] r represents 0 to 4;
[0055] each R.sup.100 is the same or different when r is 2 or more,
and represents a halogen atom, a C.sub.1-6 alkyl group optionally
substituted with a halogen atom, OR.sup.111, or a group represented
by the formula: --N(R.sup.112a)--R.sup.112b,
[0056] where R.sup.112, R.sup.112a and R.sup.112b are each
independently a hydrogen atom or a C.sub.1-6 alkyl group, and
[0057] s represents 0 to 5;
[0058] each R.sup.102 is the same or different when s is 2 or more,
and represents a halogen atom, a C.sub.1-6 alkyl group, OR.sup.113,
a group represented by the formula: --N(R.sup.114a)--R.sup.114b, a
group represented by the formula: --NH--C(.dbd.O)--R.sup.115, a
group represented by the formula: --C(.dbd.O)--R.sup.116, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, a nitro group, or a cyano group,
[0059] where R.sup.113 is a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, an
optionally substituted arylalkyl group, or an optionally
substituted heteroaryl group,
[0060] R.sup.114a and R.sup.114b are each independently a hydrogen
atom or a C.sub.1-3 alkyl group,
[0061] R.sup.115 is an optionally substituted alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, or a group represented by the formula:
--NH--R.sup.121,
[0062] R.sup.116 is an optionally substituted alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, OR.sup.122, or a group represented by the
formula: --N(R.sup.123a)--R.sup.123b,
[0063] R.sup.121 is an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group, R.sup.122 is a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, or
an optionally substituted heteroaryl group, and
[0064] R.sup.123a and R.sup.123b are each independently a hydrogen
atom, an optionally substituted alkyl group, an optionally
substituted aryl group, or an optionally substituted heteroaryl
group, or R.sup.123a and R.sup.123b are linked together to form a
cyclic amine;
[0065] R.sup.103 represents a hydrogen atom, a C.sub.1-6 alkyl
group, a C.sub.3-6 cycloalkyl group, or a C.sub.3-6, cycloalkyl
C.sub.1-6, alkyl group; and
[0066] R.sup.101 and R.sup.103 are optionally linked together to
form a five- to seven-membered ring hetero ring when R.sup.101 is
present at the 8-position; and a pharmacologically acceptable salt
thereof.
[7] The anticancer agent according to any one of claims 1 to 6,
where the microtubule inhibitory compound is at least one compound
selected from the group consisting of paclitaxel, vinblastine,
vincristine, vindesine, vinorelbine, docetaxel, cabazitaxel,
eribulin and a pharmacologically acceptable salt thereof. [8] The
anticancer agent according to any one of claims 1 to 7, where the
cancer is colorectal cancer. [9] A kit for preventing and/or
treating a cancer, comprising a tankyrase inhibitor containing a
tankyrase inhibitory compound as an active ingredient and a
microtubule inhibitor containing a microtubule inhibitory compound
as an active ingredient. [10] A method for preventing and/or
treating a cancer, comprising administering to a patient a
combination of a tankyrase inhibitor containing a tankyrase
inhibitory compound as an active ingredient and a microtubule
inhibitor containing a microtubule inhibitory compound as an active
ingredient. [11] An anticancer agent for preventing and/or treating
a cancer, comprising a combination of: a tankyrase inhibitor
containing at least one tankyrase inhibitory compound selected from
the group consisting of a compound of the formula (1), a compound
of the formula (11) and a pharmacologically acceptable salt
thereof, as an active ingredient; and at least one agent selected
from the group consisting of an alkylating agent, an
antimetabolite, a plant alkaloid, a topoisomerase inhibitor, an
anticancer antibiotic and a platinating agent. [12] An anticancer
agent for preventing and/or treating a cancer, comprising a
tankyrase inhibitor containing at least one tankyrase inhibitory
compound selected from the group consisting of a compound of the
formula (1), a compound of the formula (11) and a pharmacologically
acceptable salt thereof, as an active ingredient, for use in
administration in combination with at least one agent selected from
the group consisting of an alkylating agent, an antimetabolite, a
plant alkaloid, a topoisomerase inhibitor, an anticancer antibiotic
and a platinating agent. [13] An anticancer agent for preventing
and/or treating a cancer, comprising at least one agent selected
from the group consisting of an alkylating agent, an
antimetabolite, a plant alkaloid, a topoisomerase inhibitor, an
anticancer antibiotic and a platinating agent as an active
ingredient, for use in administration in combination with a
tankyrase inhibitor containing at least one tankyrase inhibitory
compound selected from the group consisting of a compound of the
formula (1), a compound of the formula (11) and a pharmacologically
acceptable salt thereof [14] An anticancer agent for preventing
and/or treating a cancer, comprising a combination of: at least one
tankyrase inhibitory compound selected from the group consisting of
a compound of the formula (1), a compound of the formula (11) and a
pharmacologically acceptable salt thereof and at least one agent
selected from the group consisting of an alkylating agent, an
antimetabolite, a plant alkaloid, a topoisomerase inhibitor, an
anticancer antibiotic and a platinating agent, as active
ingredients. [15] A kit for preventing and/or treating a cancer,
comprising a combination of: a tankyrase inhibitor containing at
least one tankyrase inhibitory compound selected from the group
consisting of a compound of the formula (1), a compound of the
formula (11) and a pharmacologically acceptable salt thereof, as an
active ingredient; and at least one agent selected from the group
consisting of an alkylating agent, an antimetabolite, a plant
alkaloid, a topoisomerase inhibitor, an anticancer antibiotic and a
platinating agent. [16] A method for preventing and/or treating a
cancer, comprising a combination of: a tankyrase inhibitor
containing at least one tankyrase inhibitory compound selected from
the group consisting of a compound of the formula (1), a compound
of the formula (11) and a pharmacologically acceptable salt
thereof, as an active ingredient; and at least one agent selected
from the group consisting of an alkylating agent, an
antimetabolite, a plant alkaloid, a topoisomerase inhibitor, an
anticancer antibiotic and a platinating agent.
[0067] The reason why the above purpose can be achieved by the
present invention is not necessarily clear, but the present
inventors infer as follows. That is, in the present invention, a
combination of a tankyrase inhibitory compound and a microtubule
inhibitory compound is used, but regarding tankyrase, according to
Ha et al. (Ha et al., Cell Death Differ., 19:321-332, 2012),
tankyrase increases protein stability and poly(ADP-ribosyl)ation
activity (PARP activity) by phosphorylation by the kinase Plk1
during mitosis. A mutant tankyrase in which four threonines and one
serine are all replaced by alanine, which are assumed to be the
phosphorylation site of Plk1, does not undergo phosphorylation by
Plk1 and it decrease protein stability and PARP activity. Tankyrase
is localized at telomeres at the ends of chromosomes throughout the
cell cycle and at spindle poles during cell division stage, but
this mutant tankyrase is not localized at either telomeres or
spindle poles. On the other hand, it has been reported that at the
cell division stage, tankyrases are essential for the resolution of
telomeric cohesions between sister chromatids (Dynek and Smith,
Science, 304:97-100, 2004). It has also been reported that
localization of tankyrases at spindle poles and PARP activity are
essential for normal structure organization and functional
expression of the mitotic spindle (Chang et al., Nat Cell Biol.
2005; 7:1133-1139). Therefore, the present inventors presume that
tankyrase, which is inhibited by the above tankyrase inhibitory
compounds, contributes to the progression of cell division by
increasing its own stability and PARP activity through selective
phosphorylation during cell division stage and exerting intrinsic
functions at telomeres and spindle poles.
[0068] By the way, the above microtubule inhibitory compounds
prevent cell mitosis by inhibiting microtubule polymerization or
depolymerization, thereby exerting a cytocidal effect. Because
microtubule inhibition keeps the cell cycle in cell division stage,
tankyrase phosphorylate, stabilization, and increased PARP activity
are observed in cells treated with microtubule inhibitory compounds
(Ha et al.,). Therefore, according to the combination of a
tankyrase inhibitory compound and a microtubule inhibitory compound
of the present invention, the microtubule inhibitory compound may
retain the cell cycle in cell division stage to increase the
functional requirement of tankyrase at the spindle poles and
telomeres, while inhibiting the function of tankyrase by the
tankyrase inhibitor compound, so that synergistic cytocidal effects
can be achieved compared with the single drug treatment of each of
them, and they may be effective in the treatment and/or prevention
of proliferative diseases such as cancer.
[0069] The present invention can provide a novel anticancer agent
and a kit useful for treating and/or preventing proliferative
diseases such as a cancer.
BRIEF EXPLANATION OF DRAWINGS
[0070] FIG. 1A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 1.
[0071] FIG. 1B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 1.
[0072] FIG. 1C is a graph showing the result by conducting MTT
assay (vincristine) on Example 1.
[0073] FIG. 1D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 1.
[0074] FIG. 2A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 2.
[0075] FIG. 2B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 2.
[0076] FIG. 2C is a graph showing the result by conducting MTT
assay (vincristine) on Example 2.
[0077] FIG. 2D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 2.
[0078] FIG. 3A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 3.
[0079] FIG. 3B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 3.
[0080] FIG. 3C is a graph showing the result by conducting MTT
assay (vincristine) on Example 3.
[0081] FIG. 3D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 3.
[0082] FIG. 4A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 4.
[0083] FIG. 4B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 4.
[0084] FIG. 4C is a graph showing the result by conducting MTT
assay (vincristine) on Example 4.
[0085] FIG. 4D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 4.
[0086] FIG. 5A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 5.
[0087] FIG. 5B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 5.
[0088] FIG. 5C is a graph showing the result by conducting MTT
assay (vincristine) on Example 5.
[0089] FIG. 5D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 5.
[0090] FIG. 6A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 6.
[0091] FIG. 6B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 6.
[0092] FIG. 6C is a graph showing the result by conducting MTT
assay (vincristine) on Example 6.
[0093] FIG. 6D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 6.
[0094] FIG. 7A is a graph showing the result by conducting MTT
assay (docetaxel) on Example 7.
[0095] FIG. 7B is a graph showing the result by conducting MTT
assay (paclitaxel) on Example 7.
[0096] FIG. 7C is a graph showing the result by conducting MTT
assay (vincristine) on Example 7.
[0097] FIG. 7D is a graph showing the result by conducting MTT
assay (vinblastine) on Example 7.
[0098] FIG. 8A is a graph showing the result by conducting MTT
assay ((a), (b), (c), (d), (e), and (f)) on Example 8.
[0099] FIG. 8B is a graph showing the result by conducting MTT
assay ((a), (b), (c), (d), (e), and (f)) on Example 8.
[0100] FIG. 8C is a graph showing the result by conducting MTT
assay ((a), (b), (c), (d), (e), and (f)) on Example 8.
[0101] FIG. 9 is a graph showing the result by conducting MTT assay
(irinotecan) on Example 9.
[0102] FIG. 10 is a graph showing the result by conducting MTT
assay (irinotecan) on Example 10.
[0103] FIG. 11 is a graph showing the result by conducting MTT
assay (irinotecan) on Example 11.
[0104] FIG. 12 is a graph showing the result by conducting MTT
assay (irinotecan) on Example 12.
[0105] FIG. 13 is a graph showing the result by conducting MTT
assay (irinotecan) on Example 13.
[0106] FIG. 14 is a graph showing the result by conducting MTT
assay (irinotecan) on Example 14
DESCRIPTION OF EMBODIMENTS
[0107] The present invention relates to an anticancer agent for
treating and/or preventing cancer, containing a combination of a
tankyrase inhibitor containing a tankyrase inhibitory compound as
an active ingredient and a microtubule inhibitor containing a
microtubule inhibitory compound as an active ingredient;
[0108] an anticancer agent for preventing and/or treating a cancer,
containing a tankyrase inhibitory compound as an active ingredient,
for use in administration in combination with a microtubule
inhibitor containing a microtubule inhibitory compound;
[0109] an anticancer agent for preventing and/or treating a cancer,
containing a microtubule inhibitory compound as an active
ingredient, for use in administration in combination with a
tankyrase inhibitor containing a tankyrase inhibitory compound;
[0110] an anticancer agent for preventing and/or treating a cancer,
containing a tankyrase inhibitory compound and a microtubule
inhibitory compound as active ingredients; and
[0111] a kit for preventing and/or treating a cancer, composed of a
tankyrase inhibitor containing a tankyrase inhibitory compound and
a microtubule inhibitor containing a microtubule inhibitory
compound.
[0112] In the present invention, the "treatment and/or prevention
of cancer" and the "anticancer" include not only direct treatment
by cytotoxic effects or cell proliferation inhibitory effects on
cancer cells, but also anticancer actions in a broad sense, such as
suppression of invasion and metastasis of cancer cells and
suppression of tumor angiogenesis, and the "anticancer agent"
refers to an agent which exhibits at least one of these actions.
Examples of the proliferative diseases include, but are not limited
to, various solid tumors and blood tumors, for example malignant
tumors such as fibrosarcoma, ovary cancer, glioblastoma, pancreatic
cancer, breast cancer, astrocytoma, lung cancer, gastric cancer,
liver cancer, colorectal cancer, bladder cancer and leukemia.
Treatment and prevention of the proliferative diseases includes
killing of tumor cells of the malignant tumors; and suppression,
prevention and retardation of proliferation and metastasis of the
tumor cells.
[0113] In the present invention, the term "pharmacologically
acceptable" means being suitable for pharmacological use, and
pharmacologically acceptable salts according to the present
invention include, but are not particularly limited to, salts of
alkali metals or alkali earth metals such as sodium, potassium and
calcium; salts of hydrohalic acids such as hydrofluoric acid,
hydrochloric acid, hydrobromic acid and hydroiodic acid; salts of
inorganic acids such as sulfuric acid, nitric acid, phosphoric
acid, perchloric acid and carbonic acid; salts of organic
carboxylic acids such as formic acid, acetic acid, trifluoroacetic
acid, trichloroacetic acid, hydroxyacetic acid, propionic acid,
lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid,
mandelic acid, butyric acid, fumaric acid, succinic acid, maleic
acid and malic acid; salts of acidic amino acids such as aspartic
acid and glutamic acid; salts of sulfonic acids such as
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and
toluenesulfonic acid; adducts such as acetone, methylethylketone,
ether, ethyl acetate; and solvates such as hydrates and
alcoholates.
[0114] In the present invention, the "hydrogen atoms" in the
formulae include deuterium atoms (D) unless otherwise specified.
The "halogen atoms" in the formulae include fluorine atoms,
chlorine atoms, bromine atoms and iodine atoms.
[0115] In the formulae according to the present invention, the
"alkyl group" refers to a linear or branched saturated hydrocarbon
group having 1 to 8 carbon atoms, and the "C.sub.1-3 alkyl group"
and the "C.sub.1-6, alkyl group" mean that the alkyl groups have 1
to 3 carbon atoms and 1 to 6 carbon atoms, respectively. Examples
of the linear or branched saturated hydrocarbon group generally
include, but are not particularly limited to, groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl groups.
[0116] In the formulae according to the present invention, the
"aryl group" refers to a six-membered ring monocyclic aromatic
hydrocarbon group consisting of only carbon atoms, or a fused-ring
aromatic hydrocarbon group in which two or more such six-membered
ring monocyclic aromatic hydrocarbon groups are fused. Examples of
the aryl group generally include, but are not particularly limited
to, groups such as phenyl and naphthyl groups.
[0117] In the formulae according to the present invention, the
"heteroaryl group" refers to a group derived from a five- or
six-membered ring monocyclic aromatic heterocycle having 1 to 4
hetero atoms selected from the group consisting of a nitrogen atom,
an oxygen atom and a sulfur atom; a group derived from a fused-ring
aromatic heterocycle in which a five- or six-membered ring
monocyclic aromatic heterocycle having 1 to 4 hetero atoms is fused
with a six-membered ring monocyclic aromatic ring consisting of
only carbon atoms; or a group derived from a fused-ring aromatic
heterocycle in which a five- or six-membered ring monocyclic
aromatic heterocycle having 1 to 4 hetero atoms is fused with a
five- or six-membered ring monocyclic aromatic heterocycle having 1
to 4 hetero atoms. Examples of the heteroaryl group generally
include, but are not particularly limited to, groups such as
pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, imidazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridyl, pyridazinyl,
pyrazyl, pyrimidyl, benzothienyl, benzofuryl, indolyl, isoindolyl,
benzoimidazolyl, benzopyrazolyl, benzothiazolyl, benzooxazolyl,
benzotriazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,
phthalazinyl, imidazo[5,1-b]thiazolyl and
1H-pyrrolo[2,3-b]pyridinyl groups, each of which has a binding site
at any possible position.
[0118] In the formulae according to the present invention, the
"cycloalkyl group" refers to a cyclic saturated hydrocarbon group
(cyclic hydrocarbon group) having 3 to 8 carbon atoms, and the
cyclic hydrocarbon group may be a monocyclic ring, or may form a
fused ring, a crosslinked ring or a spiro ring. The "C.sub.3-3
cycloalkyl group" means that the cycloalkyl group has 3 to 8 carbon
atoms. Examples of the cyclic saturated hydrocarbon group generally
include, but are not particularly limited to, groups such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl,
bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.3.0]octyl,
bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl,
bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl,
spiro[3.3]heptyl and spiro[3.4]octyl groups, each of which has a
binding site at any possible position.
[0119] In the formulae according to the present invention, the
"heterocycloalkyl group" refers to a 3 to 7-membered ring saturated
heterocycle or unsaturated heterocycle other than an aromatic ring,
which has 1 to 4 hetero atoms selected from the group consisting of
a nitrogen atom, an oxygen atom and a sulfur atom, and the cyclic
hydrocarbon group may be a monocyclic ring, or may form a
crosslinked ring or a spiro ring, and is optionally substituted
with any one or more substituents defined herein. Examples of the
heterocycloalkyl group include, but are not particularly limited
to, groups such as oxetanyl, tetrahydrofuryl, dihydrofuryl,
dihydropyranyl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl,
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
1,1-dioxide thiomorphorinyl, dioxopiperidinyl, diazepanyl,
morphorinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl,
pyrrolinyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl,
1,4-dithianyl, oxathianyl, thiomorphorinyl,
3,6-diazabicylo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl,
3,8-diazabicyclo[3.2.1]octyl, 3,9-diazabicyclo[3.3.1]nonyl and
2-oxa-7-azaspiro[3.5]nonyl groups, each of which has a binding site
at any possible position.
[0120] In the formulae according to the present invention, the
"hetero ring" refers to an unsaturated heterocycle other than an
aromatic ring, which has 1 to 4 hetero atoms selected from the
group consisting of a nitrogen atom, an oxygen atom and a sulfur
atom, and the hetero ring is preferably five- to seven-membered
ring, more preferably five- or six-membered ring. The heterocycle
may be a monocyclic ring, or may form a crosslinked ring or a spiro
ring. Examples of the hetero ring include, but are not limited to,
rings such as 2,3-dihydro-1H-pyrrole, 2,3-dihydroxazole,
2,3-dihydro-1H-imidazole, 1,2,3,4-tetrahydropyridine,
2,3,4,5-tetrahydro-1H-azepine, 3,4-dihydro-2H-1,4-oxazine,
1,2,3,4-tetrahydropyrazine, 3,4-dihydro-2H-1,4-thiazine and
4,5,6,7-tetrahydro-1,4-oxazepine rings, each of which has a binding
site at any possible position.
[0121] In the formulae according to the present invention, the
"arylalkyl group", the "heteroarylalkyl group", the
"cycloalkylalkyl group" or the "heterocycloalkylalkyl group" refers
to a group (a group represented by the formula: -Ak.sup.1-Ar.sup.1)
in which an aryl group, a heteroaryl group, a cycloalkyl group or a
heterocycloalkyl group (represented by the formula: --Ar.sup.1) as
defined herein is bonded at a binding site at any possible position
to a binding site at any possible position in an alkyl group
(represented by the formula: -Ak.sup.1) as defined herein. For
example, the "C.sub.1-3 alkyl" in the "aryl C.sub.1-3 alkyl group",
the "heteroaryl C.sub.1-3 alkyl group", the "C.sub.3-8 cycloalkyl
C.sub.1-3 alkyl group" and the "heterocycloalkyl C.sub.1-3 alkyl
group" means that the alkyl group has 1 to 3 carbon atoms, and the
"C.sub.3-7 cycloalkyl" in the "C.sub.3-9 cycloalkyl C.sub.1-3 alkyl
group" means that the cycloalkyl group has 3 to 8 carbon atoms.
[0122] In the formulae according to the present invention, the
"C.sub.1-3 alkyloxy group" or the "aryloxy group" refers to a group
(a group represented by the formula: --O-Ak.sup.2 or a group
represented by the formula: --O--Ar.sup.2) in which a C.sub.1-3
alkyl group (represented by the formula: -Ak.sup.2) or an aryl
group (represented by the formula: --Ar.sup.2) as defined herein is
bonded to an oxygen atom.
[0123] In the formulae according to the present invention, the
"di-C.sub.1-3 alkylamino group" refers to a group (a group
represented by the formula: --N(.about.Ak.sup.3)-Ak.sup.4) in which
two C.sub.1-3 alkyl groups (represented by the formulae: -Ak.sup.3
and -Ak.sup.4) which are the same or different as defined herein
are bonded to a nitrogen atom, and the "arylamino group" refers to
a group (a group represented by the formula: --N--Ar.sup.3) in
which an aryl group (represented by the formula: Ar.sup.3) as
defined herein is bonded to an amino group.
[0124] In the formulae according to the present invention, the
"cyclic amine" refers to a nitrogen-containing heterocycle having 3
to 8 atoms, and the nitrogen-containing heterocycle may be a
monocyclic ring, or may form a fused ring, a crosslinked ring or a
spiro ring. Examples of the cyclic amine include, but are not
particularly limited to, azetidine, pyrrolidine, piperidine,
piperazine, morpholine, thiomorpholine, pyrazole, imidazole,
triazole, azepane, azepine and azocane.
[0125] In the formulae according to the present invention, the term
"optionally substituted" means that unless otherwise specified, any
hydrogen atom bonded to a group described as being optionally
substituted is substituted with a substituent (atom or group)
selected from the group consisting of other atoms or groups, and
the number of positions at which the hydrogen atom is substituted
may be 1 or more. When the number of positions at which the
hydrogen atom is substituted is 2 or more, the substituents are the
same or different.
[0126] The compound according to the present invention may have one
or more asymmetric carbon atoms, and optically active substances,
enantiomers, any mixtures thereof, racemates and the like based on
the one or more asymmetric carbon atoms are all within the scope of
the present invention. The group having an unsaturated double bond
can be present in a cis- or trans-form. Further, the compound
according to the present invention expresses a form of one of
possible isomers (rotational isomers, atropisomers and tautomers)
in addition to the above-described isomers, and these isomers may
be present singly, or present as a mixture thereof. Herein, a
compound which has any of the above-described isomers and isotopes
and whose name is not particularly specified may be one of the
isomers and isotopes, or a mixture or a racemate of two or more of
the isomers and isotopes.
[0127] <Tankyrase Inhibitory Compound>
[0128] In the present invention, the tankyrase inhibitory compound
is a compound having tankyrase inhibitory activity. The tankyrase
inhibitory compound is preferably a compound which inhibits
tankyrase activity by binding to at least one of a nicotinamide
binding pocket and an adenosine binding pocket being a site to
which NAD+ as a substrate of tankyrase binds. As the tankyrase
inhibitory compound according to the present invention, one that
acts on at least one of the nicotinamide binding pocket and the
adenosine binding pocket can be used. More specifically, the
tankyrase inhibitory compound may be any of a nicotinamide-type
compound which acts on the nicotinamide binding pocket; an
adenosine-type compound which acts on the adenosine binding pocket;
and a dual-type compound which acts on both the nicotinamide
binding pocket and the adenosine binding pocket.
[0129] In the present invention, whether the tankyrase inhibitory
compound is a nicotinamide-type compound or an adenosine-type
compound can be determined by X-ray diffraction, more specifically
a method in which a complex is crystallized from a mixed liquid of
a tankyrase crystal prepared beforehand and the tankyrase
inhibitory compound, and subjected to X-ray diffraction (soaking
method), or a method in which a complex is crystallized from a
mixed liquid having the tankyrase inhibitory compound coexisting
with tankyrase in a state before the crystallization, and subjected
to X-ray diffraction (co-crystallization). Whether the tankyrase
inhibitory compound is a dual-type compound can be determined by
preparing a crystal under any one of the above-described
conditions, and performing X-ray diffraction.
[0130] Examples of the nicotinamide-type tankyrase inhibitory
compound include compounds of the following formula (1) and
pharmacologically acceptable salts thereof (hereinafter, sometimes
referred to as "spiro compounds"), and compounds of the following
formula (11) and pharmacologically acceptable salts thereof
(hereinafter, sometimes referred to as "dihydroquinazolinone-based
compounds"). One of these compounds may be used alone, or two or
more thereof may be used in combination.
(Spiro Compound)
[0131] The nicotinamide-type tankyrase inhibitory compound
according to the present invention is a compound of the following
formula (1) or a pharmacologically acceptable salt thereof (spiro
compound):
##STR00003##
[0132] where A.sup.1, A.sup.2, A.sup.3 and A.sup.4 form a structure
in which A.sup.1 and A.sup.1 each represent a single bond, one of
A.sup.1 and A.sup.2 represents a single bond and the other
represents CH.sub.2, or A.sup.1 represents a single bond and
A.sup.4 represents CH.sub.2,
[0133] with the proviso that one of A.sup.3 and A.sup.4 is CH.sub.2
or CO and the other is O or NR when A.sup.1 and A each represent a
single bond or A.sup.1 represents CH-- and A.sup.2 represents a
single bond, one of A.sup.3 and A.sup.4 is NR.sup.1 and the other
is CH.sub.2 or CO when A.sup.1 represents a single bond and A.sup.2
represents CH.sub.2, and one of A.sup.2 and A.sup.3 is NR.sup.1 and
the other is CH.sub.2 or CO when A.sup.1 represents a single bond
and A.sup.4 represents CH.sub.2,
[0134] where R.sup.1 represents a hydrogen atom, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
heteroaryl, an optionally substituted C.sub.3-8 cycloalkyl
C.sub.1-3 alkyl group, an optionally substituted aryl C.sub.1-3
alkyl group, an optionally substituted heteroaryl C.sub.1-3 alkyl
group, an optionally substituted three- to seven-membered ring
heterocycloalkyl C.sub.1-3, alkyl group, a group represented by the
formula: --(CH.sub.2).sub.m--C(.dbd.O)-L, or a group represented by
the formula: --S(.dbd.O).sub.2--R.sup.13,
[0135] m is 0, 1, 2 or 3, L is R.sup.12 when m is O, and L is
R.sup.12 when m is 1, 2 or 3,
[0136] R.sup.11 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, OR.sup.51, a group represented by the
formula: --C(.dbd.O)--OR.sup.52, or a group represented by the
formula: --N(R.sup.53a)--R.sup.53b,
[0137] R.sup.51 is an optionally substituted aryl C.sub.1-3 alkyl
group,
[0138] R.sup.52 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group,
[0139] R.sup.53a and R.sup.53b are each independently a hydrogen
atom or an optionally substituted C.sub.1-6 alkyl group, or
R.sup.53a and R.sup.53b are linked together to form a three- to
seven-membered ring heterocycloalkyl group optionally containing at
least one atom or group selected from the group consisting of an
oxygen atom, a sulfur atom and NR.sup.81,
[0140] R.sup.81 is a hydrogen atom or an optionally substituted
C.sub.1-3 alkyl group,
[0141] R.sup.12 is an optionally substituted aryl group, OR.sup.54,
or a group represented by the formula:
--N(R.sup.55a)--R.sup.55b,
[0142] R.sup.54 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted aryl C.sub.1-3
alkyl group, or an optionally substituted heteroaryl C.sub.1-3
alkyl group,
[0143] R.sup.55a and R.sup.55b are each independently a hydrogen
atom, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted aryl C.sub.1-3 alkyl group, an optionally
substituted heteroaryl C.sub.1-3 alkyl group, or a group
represented by the formula: --(C.dbd.O)--R.sup.82, or R.sup.55a and
R.sup.55b are linked together to form a three- to seven-membered
ring heterocycloalkyl group optionally containing at least one atom
or group selected from the group consisting of an oxygen atom, a
sulfur atom and NR.sup.83, or form an optionally substituted
6,8-dihydro-5H-imidazolo[1,2-a]pyrazin-7-yl group,
[0144] R.sup.82 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, or an optionally substituted aryl C.sub.1-3
alkyl group,
[0145] R.sup.83 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group, and
[0146] R.sup.13 is an optionally substituted C.sub.1-6 alkyl group;
the structure formed by E.sup.1, E.sup.2, E.sup.3 and E.sup.4 is a
group represented by the formula: -E.sup.1-E.sup.2-E.sup.3-E.sup.4-
(where the bonds between E.sup.1, E.sup.2, E.sup.3 and E.sup.4 are
single bonds or double bonds) in which E.sup.1 is N or CR.sup.2,
E.sup.2 is N or CR.sup.3, E.sup.3 is N or CR.sup.4 and E.sup.4 is N
or CR.sup.3, a group represented by the formula:
-E.sup.2-E.sup.3=E.sup.4- in which E.sup.2 is O or S and each of
E.sup.3 and E.sup.4 is CH with E.sup.1 representing a single bond,
or a group represented by the formula: -E.sup.2=E.sup.3-E.sup.4- in
which each of E.sup.2 and E.sup.3 is CH and E.sup.4 is O or S with
E representing a single bond,
[0147] where R.sup.2, R.sup.1, R.sup.4 and R.sup.5 are each
independently a hydrogen atom, a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom, a cyano group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted aryl
group, an optionally substituted heteroaryl group, an optionally
substituted three- to seven-membered ring heterocycloalkyl group,
or a group represented by the formula:
-Q-(CH.sub.2).sub.n--R.sup.14,
[0148] n is 0, 1, 2 or 3,
[0149] Q is a group of the formula: --CH.dbd.CH--, O, CO, a group
represented by the formula: --C(.dbd.O)--O--, a group represented
by the formula: --C(.dbd.O)--N(R.sup.56)--, NR.sup.56, a group
represented by the formula: --N(R.sup.5b)--C(.dbd.O)--, or a group
represented by the formula: --N(R.sup.5)--C(.dbd.O)--O--,
[0150] R.sup.56 is a hydrogen atom, an optionally substituted
C.sub.1-3 alkyl group, or a group represented by the formula:
--C(.dbd.O)--R.sup.84,
[0151] R.sup.84 is a hydrogen atom, an optionally substituted
C.sub.1-5 alkyl group, an optionally substituted aryl group, an
optionally substituted C.sub.1-6 alkyloxy group, or an optionally
substituted aryloxy group, and
[0152] R.sup.14 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally substituted
C.sub.3-8 cycloalkyl group, or an optionally substituted three- to
seven-membered ring heterocycloalkyl group; and
[0153] the structure formed by G.sup.1, G.sup.2, G.sup.3 and
G.sup.4 is a group represented by the formula:
-G.sup.1-G.sup.2-G.sup.3-G.sup.4- (where the bonds between G.sup.1,
G.sup.2, G.sup.3 and G.sup.4 are single bonds or double bonds)
which is represented by the formula: --CH.dbd.CH--CH.dbd.CR.sup.6--
(with the exception of cases where A.sup.1 and A.sup.2 each
represent a single bond, with A.sup.3 being O and A.sup.4 being
CO), the formula: --CH.dbd.CH--CH.dbd.N-- (with the exception of
cases where A.sup.1 and A.sup.2 each represent a single bond, with
A.sup.3 being O and A.sup.4 being CO), the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CO--CH.sub.2--CH.sub.2--N(R)--, the formula:
--CH.sub.2--CF.sub.2--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--O--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--S--CH.sub.2--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--N(R.sup.7)--CH.sub.2--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--O--, the formula:
--CH.sub.2--CH.sub.2--CH.sub.2--N(R')-- or the formula:
--O--CH.sub.2--CH.sub.2--N(R')--, or a group represented by the
formula: -G.sup.2-G.sup.3-G.sup.4- (where the bonds between
G.sup.2, G.sup.3 and G.sup.4 are single bonds or double bonds)
which is represented by the formula: --CH.dbd.CH--N(R.sup.7)--, the
formula: --CH.sub.2--CH.sub.2--N(R.sup.7)--, the formula:
--N.dbd.CH--N(R.sup.7)-- or the formula: --N(R.sup.7)--CH.dbd.N--,
with G.sup.1 representing a single bond,
[0154] where R.sup.6 is a hydrogen atom, a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom, an optionally
substituted C.sub.1-6 alkyl group, or an optionally substituted
C.sub.1-6 alkyloxy group,
[0155] R.sup.7 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.3-8
cycloalkyl group, an optionally substituted C.sub.3-8 cycloalkyl
C.sub.1-3 alkyl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl group, optionally substituted
three- to seven-membered ring heterocycloalkyl C.sub.1-3 alkyl
group, a group represented by the formula:--C(.dbd.O)--R.sup.15, or
a group represented by the formula
--(CH.sub.2).sub.p--C(.dbd.O)--OR.sup.16,
[0156] p is 0, 1, 2 or 3,
[0157] R.sup.15 is a hydrogen atom, an optionally substituted
C.sub.1-6 alkyl group or OR.sup.57,
[0158] R.sup.57 is an optionally substituted C.sub.1-6 alkyl group,
or an optionally substituted aryl C.sub.1-3 alkyl group, and
[0159] R.sup.16 is a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group.
[0160] When used in combination with any of anticancer agents other
than the following microtubule inhibitory compounds, more
specifically alkylating agents (e.g., temozolomide and melphalan),
antimetabolites (e.g., gemcitabine, cytarabine (Ara-C),
fluorouracil (5-FU), pemetrexed, mercaptopurine and methotrexate),
plant alkaloids (the "plant alkaloids" in the present invention
includes analogues in which some of atoms of the plant alkaloid are
substituted with other atoms (e.g., irinotecan (SN-38) and
etoposide (VP-16))), topoisomerase inhibitors (which include
irinotecan (SN-38) and etoposide (VP-16)), agents serving as both a
plant alkaloid and a topoisomerase inhibitor (including agents
serving as both an analogue of a plant alkaloid and a topoisomerase
inhibitor (e.g., irinotecan (SN-38) and etoposide (VP-16))),
anticancer antibiotics (e.g., actinomycin D, daunorubicin,
doxorubicin, bleomycin and mitoxantrone) and platinating agents
(e.g., oxaliplatin, carboplatin and cisplatin), the spiro compound
exhibits an excellent anticancer action without causing inhibition
of each other's anticancer action. When used in combination with
any of the following microtubule inhibitory compounds, the spiro
compound exhibits a further excellent synergistic anticancer
action.
[0161] In the formula (1), A.sup.1, A.sup.1, A.sup.3 and A.sup.4
form a structure in which A and A.sup.2 each represent a single
bond, one of A.sup.1 and A.sup.2 represents a single bond and the
other represents CH.sub.2, or A.sup.1 represents a single bond and
A.sup.4 represents CH.sub.2. When A.sup.1 and A.sup.2 each
represent a single bond, A.sup.3 is CH.sub.L or CO and A is O or
NR.sup.1, or A.sup.3 is O or NR.sup.1 and A.sup.4 is CH.sub.2 or
CO. When A.sup.1 represents CH.sub.2 and A.sup.2 represents a
single bond, A.sup.3 is CH.sub.2 or CO and A.sup.4 is O or
NR.sup.1, or A.sup.3 is O or NR.sup.1 and A.sup.4 is CH.sub.2 or
CO. When A.sup.1 represents a single bond and A.sup.2 represents
CH.sub.2, A.sup.3 is NR and A.sup.1 is CH.sub.2 or CO, or A.sup.3
is CH.sub.2 or CO and A.sup.4 is NR.sup.1. Further, when A.sup.1
represents a single bond and A.sup.4 represents CH.sub.2, A.sup.2
is NR.sup.1 and A.sup.3 is CH.sub.2 or CO, or A.sup.2 is CH.sub.2
or CO and A.sup.3 is NR.sup.1.
[0162] In the formula (1), the structure formed by A.sup.1,
A.sup.2, A.sup.3 and A.sup.4 is preferably a structure in which
A.sup.1 and A.sup.2 each represent a single bond; more preferably a
structure in which one of A.sup.3 and A.sup.4 is CH.sub.2 or CO and
the other is O or NR.sup.1; still more preferably a structure in
which A.sup.3 is O, CH.sub.2 or CO and A.sup.4 is CO or NR.sup.1
(with the exception of cases where each of A.sup.3 and A.sup.4 is
CO, where A.sup.3 is CH.sub.2 and A.sup.4 is CO, and where A.sup.3
is O and A.sup.4 is NR.sup.1); especially preferably a structure in
which the combination of A.sup.3 and A.sup.4 is a combination of O
and CO, CH.sub.2 and NR.sup.1 or CO and NR.sup.1.
[0163] In the formula (1), the structure formed by E.sup.1,
E.sup.2, E.sup.3 and E.sup.4 is a group represented by the formula:
-E.sup.1-E.sup.2-E.sup.3-E.sup.4- (where the bonds between E.sup.1,
E.sup.2, E.sup.3 and E.sup.4 are single bonds or double bonds), or
a group represented by the formula: -E.sup.2-E.sup.3=E.sup.4- or
the formula: -E.sup.2=E.sup.3-E.sup.4- with E.sup.1 representing a
single bond. Herein, unless otherwise specified, the symbols "-"
and "=" which represent bonds between atoms and/or groups in the
structural formulae denote a single bond and a double bond,
respectively, and the bonds between E.sup.1, E.sup.2, E.sup.3 and
E.sup.4 in the group represented by the above formula:
-E.sup.1-E.sup.2-E.sup.3-E.sup.4- are single bonds or double bonds
depending on a combination of atoms or groups which correspond to
E.sup.1, E.sup.2, E.sup.3 and E.sup.4.
[0164] In the formula (1), the structure formed by E.sup.1,
E.sup.2, E.sup.3 and E.sup.4 is preferably a group represented by
the above formula: -E.sup.1-E.sup.2-E.sup.3-E.sup.4- (where the
bonds between E.sup.1, E.sup.2, E.sup.3 and E.sup.4 are single
bonds or double bonds); more preferably a group in which E.sup.1 is
N or CR.sup.2, E.sup.2 is N or CR.sup.3, E.sup.3 is N or CR.sup.4
and E.sup.4 is N or CR.sup.5; still more preferably a group in
which E is CR.sup.2, E.sup.2 is CR.sup.3, E.sup.3 is CR.sup.4 and
E.sup.4 is CR.sup.5; especially preferably a group in which
E.sup.1, E.sup.2, E.sup.3 and E.sup.4 (Cs of CR.sup.2, CR.sup.3,
CR.sup.4 and CR.sup.5) form a six-membered ring aromatic
hydrocarbon group with two adjacent carbon atoms.
[0165] Further, in the formula (1), the structure formed by
G.sup.1, G.sup.2, G.sup.3 and G.sup.4 is a group represented by the
formula: -G.sup.1-G.sup.2-G.sup.3-G.sup.4- (where the bonds between
G.sup.1, G.sup.2, G.sup.3 and G.sup.4 are single bonds or double
bonds), or a group represented by the formula:
-G.sup.2-G.sup.3-G.sup.4- (where the bonds between G.sup.2, G.sup.3
and G.sup.4 are single bonds or double bonds) with G.sup.1
representing a single bond. In both the group represented by the
formula: -G.sup.1-G.sup.2-G.sup.3-G.sup.4- and the group
represented by the formula: -G.sup.2-G.sup.3-G.sup.4-, the bonds
between G.sup.1, G.sup.2, G.sup.3 and G.sup.4 are single bonds or
double bonds depending on a combination of atoms or groups which
correspond to G.sup.1, G.sup.2, G.sup.3 and G.sup.4.
[0166] In the formula (1), the structure formed by G.sup.1, G,
G.sup.3 and G.sup.4 is preferably a group represented by the above
formula: -G.sup.1-G.sup.2-G.sup.3-G.sup.4- which is represented by
the above formula: --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, the
above formula: --CH.sub.2--CF.sub.2--CH.sub.2--CH.sub.2--, the
above formula: --CH.sub.2--O--CH.sub.2--CH.sub.2--, the above
formula: --CH.sub.Z--S--CH.sub.2--CH.sub.2--, the above formula:
--CH.sub.2--CH.sub.2--CH.sub.2--O--, the above formula:
--CH.sub.2--CH.sub.2--CH.sub.2--N(R') or the above formula:
--O--CH.sub.2--CH.sub.2--N(R.sup.7)--, or a group represented by
the formula: -G.sup.2-G.sup.3-G.sup.4- (where the bonds between
G.sup.2, G.sup.3 and G.sup.4 are single bonds or double bonds)
which is represented by the formula: --CH.dbd.CH--N(R.sup.7)-- or
the formula: --CH.sub.2--CH.sub.2--N(R.sup.7)--, with G.sup.1
representing a single bond; more preferably a group represented by
the above formula: -G.sup.1-G.sup.2-G.sup.3-G.sup.4- which is
represented by the above formula:
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- or the above formula:
--CH.sub.2--CH.sub.2--CH.sub.2--N(R.sup.7)
[0167] In the formula (1), the "acyl groups in a broad sense"
include groups (groups represented by the formula:
--C(.dbd.O)--Ar.sup.4) in which a hydrogen atom, an amino group, or
a C.sub.1-6 alkyl group, an aryl group, a heteroaryl group, a
C.sub.3-8 cycloalkyl group or a heterocycloalkyl group as defined
herein (which is represented by the formula: --Ar.sup.4) is bonded
to a carbonyl group; and groups (groups represented by the formula:
--C(.dbd.O)--O--Ar.sup.5) in which a hydrogen atom, or a C.sub.1-6
alkyl group, an aryl group, a heteroaryl group, a C.sub.3-8
cycloalkyl group or a heterocycloalkyl group as defined herein
(which is represented by the formula: --Ar.sup.5) is bonded to a
carbonyl group via an oxygen atom. The acyl group is optionally
substituted with any one or more substituents as defined herein.
Examples of the acyl groups in a broad sense generally include, but
are not limited to, groups such as formyl, acetyl, propionyl,
butyroyl, valeroyl, pivaloyl, trifluoroacetyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, hydroxyacetyl, phenylacetyl,
benzoyl, naphthoyl, furoyl, thenoyl, nicotinoyl, isonicotinoyl,
methoxycarbonyl, trichloromethoxycarbonyl, ethoxycarbonyl,
tert-butyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl and
4-nitrobenzyloxycarbonyl groups. Examples of the acyl group also
include groups represented by the formula:
--C(.dbd.O)--N(R.sup.58a)--R.sup.58b [where R.sup.58a and R.sup.58b
each independently a hydrogen atom, a C.sub.1-6 alkyl group, or a
group represented by the formula: --S(.dbd.O).sub.2--CH.sub.3], and
carboxy groups (--COOH).
[0168] In the formula (1), examples of the optional substituents
include substituents such as halogen atoms (fluorine atom, chlorine
atom, bromine atom and iodine atom), a cyano group, a hydroxyl
group, a thiol group, a nitro group, the acyl groups in a broad
sense, C.sub.1-6 alkyl groups, aryl groups, heteroaryl groups,
C.sub.3-8, cycloalkyl groups, heterocycloalkyl groups, aryl
C.sub.1-3 alkyl groups, heteroaryl C.sub.1-3 alkyl groups,
C.sub.3-8 cycloalkyl C.sub.1-3 alkyl groups and heterocycloalkyl
C.sub.1-3 alkyl groups; substituents in which the acyl group, a
C.sub.1-6 alkyl group (alkoxy group or alkylthio group), an aryl
group, an aryl C.sub.1-3 alkyl group, a heteroaryl group, a
C.sub.3-8 cycloalkyl group, a heterocycloalkyl group, a
heterocycloalkyl C.sub.1-3 alkyl group or a group represented by
the formula: --SiR.sup.31aR.sup.31bR.sup.31c [where R.sup.31a,
R.sup.31b and R.sup.31c each independently represent a C.sub.1-6
alkyl group or an aryl group] is bonded via an oxygen atom or a
sulfur atom; substituents represented by the formula:
--N(R.sup.32a)--R.sup.32b [where R.sup.32a and R.sup.32b are each
independently a hydrogen atom, the acyl group in a broad sense, a
C.sub.1-6 alkyl group, a group represented by the formula:
--S(.dbd.O).sub.2--N(CH.sub.3).sub.2, or a group represented by the
formula: --S(.dbd.O).sub.2--CH.sub.3, or R.sup.32a and R.sup.32b
are linked together to form a three- to seven-membered ring
heterocycloalkyl group optionally containing at least one atom or
group selected from the group consisting of an oxygen atom, a
sulfur atom, SO, S(.dbd.O), and NR.sup.33 [R.sup.33 represents a
hydrogen atom or a C.sub.1-6 alkyl group]; substituents represented
by the formula: --C(NH.sub.2).dbd.NH; substituents represented by
the formula: --S(.dbd.O).sub.2--N(R.sup.59a)--R.sup.59b [where
R.sup.59a and R.sup.59b each independently represent a hydrogen
atom, the acyl group in a broad sense or a C.sub.1-6 alkyl group];
substituents represented by the formula:
--S(.dbd.O).sub.2--CH.sub.3; and substituents represented by the
formula: --P(.dbd.O)--OH. Of the substituents and groups involved
in formation of the substituents, the acyl groups in a broad sense,
alkyl groups, aryl groups, heteroaryl groups, cycloalkyl groups and
heterocycloalkyl groups may be further substituted with any
substituent as in the definition described above.
[0169] In the formula (1), when the group substituted is a
C.sub.1-6 alkyl group, a heteroaryl group, a C.sub.3-9 cycloalkyl
C.sub.1-3 alkyl group, an aryl C.sub.1-3 alkyl group, a heteroaryl
C.sub.1-3 alkyl group or a three- to seven-membered ring
heterocycloalkyl C.sub.1-3 alkyl group which is represented by
R.sup.1, the substituent is especially preferably a methoxy group
(--OCH.sub.3), a cyano group, a halogen atom or a hydroxyl
group.
[0170] In the formula (1), when the group substituted is a
C.sub.1-6 alkyl group, an aryl group, a heteroaryl group or a
three- to seven-membered ring heterocycloalkyl group which is
represented by R.sup.2, R.sup.3, R.sup.4 or R.sup.5, the
substituent is especially preferably a cyano group; a hydroxyl
group; a heterocycloalkyl group; a heterocycloalkyl C.sub.1-3 alkyl
group; an aryl C.sub.1-3 alkyl group; a carboxy group; a C.sub.1-3
alkoxy group; a primary amide group; a methoxycarbonyl group; an
acetyl group optionally substituted with a hydroxyl group; a
C.sub.1-3 alkyl group optionally substituted with a halogen atom, a
hydroxyl group or a C.sub.1-3 alkoxy group; a substituent
represented by the formula: --C(.dbd.O)--R.sup.60 [where R.sup.60
is a C.sub.1-3 alkyl group or a heterocycloalkyl group]; or a
substituent represented by the formula: --N(R.sup.32a)--R.sup.32b
[where R.sup.32a and R.sup.32b are more preferably each
independently a hydrogen atom or a C.sub.1-3 alkyl group].
[0171] In the formula (1), R.sup.1 is preferably a hydrogen atom,
an optionally substituted C.sub.1-6 alkyl group, an optionally
substituted aryl C.sub.1-3 alkyl group, an optionally substituted
heteroaryl C.sub.1-3 alkyl group or a three- to seven-membered ring
heterocycloalkyl C.sub.1-3 alkyl group; preferably a hydrogen atom,
or a C.sub.1-6 alkyl group optionally substituted with one to three
substituents selected from the group consisting of a hydroxyl
group, a C.sub.1-6 alkoxy group, a fluorine atom, a chlorine atom,
a bromine atom, an iodine group, a cyano group, a nitro group, an
aryl group, a heteroaryl group, a C.sub.3-8 cycloalkyl group, a
heterocycloalkyl group and the acyl group in a broad sense (when
two or more substituents are present, the substituents are the same
or different, and the aryl group, the heteroaryl group, the
C.sub.3-8 cycloalkyl group and the heterocycloalkyl group may be
further substituted).
[0172] More specific examples of R.sup.1 include a methyl group, an
ethyl group, a propyl group, an isopropyl group, a butyl group, an
isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl
group, an isopentyl group, a hexyl group, an isohexyl group, a
2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl
group, a 2,3-dihydroxypropyl group, a 2-hydroxy-2-methylpropyl
group, a 2-methoxyethyl group, a 3-methoxypropyl group, a
2,2,2-trifluoroethyl group, a 2-fluoroethyl group, a
2,3-difluoroethyl group, a 2-chloroethyl group, a 3-chloropropyl
group, a 2-bromoethyl group, a 2-iodoethyl group, a cyanomethyl
group, a 2-cyanoethyl group, a benzyl group, a 2-fluorophenylmethyl
group, a 2-pyridylmethyl group, a 3-pyridylmethyl group, a
4-pyridylmethyl group, a 6-chloro-3-pyridyl group, a
2-pyrimidylmethyl group, a 5-pyrimidylmethyl group, a
cyclopropylmethyl group, a 2-tetrahydrofurylmethyl group, an
amidinomethyl group and a carbamoylmethyl group.
[0173] In the formula (1), it is preferable that R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 satisfy the following condition: each of
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is a hydrogen atom, one or
two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are at least one
selected from the group consisting of a halogen atom (fluorine
atom, chlorine atom, bromine atom or iodine atom) and a cyano
group, one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted three- to
seven-membered ring heterocycloalkyl group or a group represented
by the above formula: -Q-(CH.sub.2).sub.n--R.sup.14.
[0174] The group presented by the above formula:
-Q-(CH.sub.2).sub.n--R.sup.14 is preferably a group represented by
the formula: --O--R.sup.14 or a group represented by the formula:
--C(.dbd.O)--O--R.sup.14, more preferably a group represented by
the above formula: --O--R.sup.14. Further, when one of R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 is a group represented by the above
formula: -Q-(CH.sub.2).sub.n--R.sup.14, R.sup.14 is preferably a
hydrogen atom (i.e. for example, in the case of a group represented
by the above formula: --O--R.sup.14, one of R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 is a hydroxyl group), a C.sub.1-2 alkyl group
optionally substituted with one substituent, or an optionally
substituted three- to seven-membered ring heterocycloalkyl group.
The substituent of the optionally substituted C.sub.1-2 alkyl group
is preferably a substituent represented by the formula:
--C(.dbd.O)--R.sup.61, a substituent represented by the above
formula: --S(.dbd.O).sub.2--N(R.sup.59a)--R.sup.59b, a substituent
represented by the above formula: --S(.dbd.O).sub.2--CH.sub.3, or a
substituent represented by the above formula: --P(.dbd.O)--OH.
[0175] More specifically, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
each independently a hydrogen atom, a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom, a cyano group, a hydroxyl
group, a methoxy group, an ethoxy group, a 2-hydroxyethoxy group, a
2-methoxyethoxy group, a carboxymethoxy group, a
5-tetrazolylmethoxy group, a cyanomethoxy group, a
4-piperidylmethoxy group, a 2-(N,N-dimethylamino)ethoxy group, a
3-oxetanylmethoxy group, a 2-morpholinoethoxy group, a
2-(N-methylpiperazino)ethoxy group, a 2-pyrrolizinoethoxy group, a
2-piperidinoethoxy group, a 3-pyrrolizinopropoxy group, a
3-tetrahydrofuryloxy group, a 4-tetrahydropyranyloxy group, a
4-(N-methylpiperidyl)methoxy group, a 2-hydroxy-2-methylpropoxy
group, a carbamoylmethoxy group, a piperidino group, a morpholino
group, a piperazino group, a 4-cyanopiperidino group, a
4-methoxycarbonylpiperazino group, a 3,5-dimethylmorpholino group,
a 3,5-dimethylpiperazino group, a 4-methoxypiperidino group, a
4-carboxypiperidino group, a N-methylsulfonylpiperazino group, a
4-methylsulfonylpiperidino group, a
N-2-hydroxy-2-methylpropylpiperazino group, a
N-hydroxyacetylpiperazino group, a N-acetylpiperazino group, a
N-methylpiperazino group, a N-(3-oxetanyl)piperazino group, a
4-hydroxycyclohexyl group, a 1-methylpyrazol-4-yl group, a
4-(N,N-dimethylamino)phenyl group, a 4-ethoxycarbonyloxazol-2-yl
group, a 4-(N-methylpiperazino)phenyl group, an ethoxycarbonyl
group, a N-(2-morpholinoethyl)carbamoyl group, a 2-oxazolyl group,
a 4-morpholinocarbonyloxazol-2-yl group, a
4-pyrrolizinomethyloxazol-2-yl group or a 4-carboxyoxazol-2-yl
group.
[0176] In the formula (1), R.sup.7 is preferably a hydrogen atom,
or a C.sub.1-6 alkyl group optionally substituted with one to three
substituents selected from the group consisting of a hydroxyl
group, a C.sub.1-6 alkoxy group, a fluorine atom, a chlorine atom,
a bromine atom, an iodine atom and a cyano group (when two or more
substituents are present, the substituents are the same or
different). More specifically, R.sup.2 is a hydrogen atom, a methyl
group, an ethyl group, a propyl group, an isopropyl group, a
2-hydroxyethyl group, a 3-hydroxypropyl group, a
2,2,2-trifluoroethyl group, a 2-cyanoethyl group or a
2-methoxyethyl group.
[0177] Examples of preferred aspects of compounds of the formula
(1) according to the present invention include aspects in which the
compounds of the above formula (1) are represented by the formula
(1-1):
##STR00004##
[0178] In the formula (1-1), A.sup.3 is O, CH.sub.2 or CO, and
A.sub.4 is CO or NR.sup.1, with the exception of cases where each
of A.sup.3 and A.sup.4 is CO, where A.sup.3 is CH.sub.2 and A.sup.4
is CO, and where A.sup.3 is O and A.sup.4 is NR.sup.1. R.sup.1 is
as described for the above formula (1).
[0179] In the formula (1-1), G.sup.4 is CH.sub.2 or NR.sup.7, and
R.sup.7 is a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group.
[0180] Examples of more preferred aspects of compounds of the
formula (1) according to the present invention include, but are not
particularly limited to, compounds of the formula (1-1) in which
A.sup.3 is CO or CH.sub.2, A.sup.1 is NR.sup.1 (R.sup.1 is more
preferably a hydrogen atom or a C.sub.1-5 alkyl group), R.sup.2 is
a halogen atom, and GI is NR.sup.7 (R.sup.7 is more preferably a
C.sub.1-6 alkyl group).
[0181] The compounds of the above formula (1) or pharmacologically
acceptable salts thereof (spiro compounds) can be produced through
the methods shown below. The method for producing a spiro compound
according to the present invention is not limited to the methods
shown below, and a range of the spiro compounds according to the
present invention is not limited to compounds produced by the
following production methods.
[0182] The method for producing a spiro compound according to the
present invention can be carried out by combining a wide range of
various kinds of synthesis methods known to persons skilled in the
art, methods obtained by making a modification or the like to the
synthesis methods if necessary, and the like while using starting
raw materials, precursors, reagents and solvents which are
commercially available or can be synthesized through methods known
to persons skilled in the art.
[0183] In the present invention, a method for introducing,
modifying or converting any substituent or the like can be carried
out by introducing, modifying or converting an intended substituent
itself or a group convertible to the substituent in a raw material
stage, an intermediate material stage or a final-form material
stage by combining a wide range of various kinds of synthesis
methods known to persons skilled in the art, methods obtained by
making a modification or the like to the synthesis methods if
necessary, and the like. The method can also be carried out by
appropriately changing the order of reaction steps, etc. The method
can also be carried out by appropriately employing general means
such as protection and deprotection of functional groups which are
commonly used in organic synthesis chemistry if necessary for
convenience of the reaction (e.g., methods described in, for
example, Green Wuts, PROTECTIVE GROUPS in ORGANIC SYNTHESIS THIRD
EDITION, John Wiley & Sons, Inc.).
[0184] Reaction apparatuses usable in production of the compound
include common glass reaction vessels, optionally glass-lined
metallic reaction baths, and flow reactors. Examples of cooling or
heating at the time of carrying out the reaction include air
cooling, water cooling, ice cooling, combination of a cryogen and a
cooling medium, and cooling of a reaction vessel or a reaction
mixture through a cooling medium cooled by a freezing machine, or
heating with hot water or steam, heating of a reaction vessel
directly by an electric heater or through a heating medium, and
heating by application of an ultrashort electromagnetic wave (i.e.
microwave heating). Further, cooling or heating using a Peltier
device, etc. can also be performed.
[0185] The spiro compound according to the present invention can be
prepared through, for example, the following production method 1 or
production method 2.
##STR00005##
[0186] In the above formulae (2) to (6), A.sup.1, A.sup.2, A.sup.3,
A.sup.4, E.sup.1, E.sup.2, E.sup.3, E.sup.4, G.sup.1, G.sup.2,
G.sup.3 and G.sup.4 are the same as A.sup.1, A.sup.2, A.sup.3,
A.sup.4, E.sup.1, E.sup.2, E.sup.3, E.sup.4, G.sup.1, G.sup.2,
G.sup.3 and G.sup.4, respectively, in the above formula (1). In the
above formulae (3) and (4), Y.sup.1 and Y.sup.2 each independently
represent a leaving group (the leaving group means a functional
group with a leaving ability which is known to persons skilled in
the art, and examples thereof include protective groups described
in, for example, Green Wuts, PROTECTIVE GROUPS in ORGANIC SYNTHESIS
THIRD EDITION, John Wiley & Sons, Inc.). Further, in the above
formulae (4) and (5), R.sup.34a and R.sup.34b each independently
represent a hydrogen atom or the protective group. Further, in the
above formula (2), R.sup.3b represents a hydrogen atom or the
protective group, and in the above formula (6), R.sup.36 represents
an optionally substituted C.sub.1-6 alkyl group.
[0187] A compound of the formula (2) (hereinafter, referred to as
an "intermediate (2)") and a compound of the formula (3)
(hereinafter, referred to as a "raw material (3)") in the
production method 1 and the intermediate (2) and compounds of the
formulae (4) and (6) (hereinafter, referred to as a "raw material
(4)" and a "raw material (6)", respectively) in the production
method 2 can be synthesized using commercially available reagents,
or known methods or methods based on the known methods. The
intermediate (2) may have a protective group if necessary, and the
protective group can be deprotected if necessary in any stage.
[0188] In the production method 1, the intermediate (2) and the raw
material (3) are dissolved or suspended in an appropriate solvent,
and reacted in the presence or non-presence of a metal catalyst and
a ligand thereof and in the presence or non-presence of a base to
produce a spiro compound according to the present invention (a
compound of the formula (1) or a salt thereof; hereinafter,
sometimes referred to as a "compound (1)").
[0189] In the production method 1, the intermediate (2) and the raw
material (3) are used normally at a molar ratio in the range of 1:1
to 3, preferably at a molar ratio in the range of 1:1 to 1.5.
[0190] Examples of the solvent to be used in the production method
1 include protic solvents such as water and alcohols (e.g.,
ethanol); hydrocarbon-based solvents such as petroleum ether,
nonaromatic hydrocarbons (e.g., n-hexane) and aromatic hydrocarbons
(e.g., toluene); halogen-based solvents such as halogenated (e.g.,
chlorinated or fluorinated) aromatic hydrocarbons (e.g.,
chlorobenzene) or nonaromatic hydrocarbons (e.g.,
1,2-dichloroethane); chain ether-based solvents (e.g.,
1,2-dimethoxyethane) or cyclic ether-based solvents (e.g.,
1,4-dioxane); ester-based solvents (e.g., ethyl acetate); and
aprotic polar solvents (e.g., acetonitrile and
N,N-dimethylformamide), and one of these solvents can be used
alone, or two or more thereof can be mixed at an appropriate ratio
and used. Of these, at least one of toluene, ethanol, 1,4-dioxane
and N,N-dimethylformamide is preferable as the solvent.
[0191] Examples of the metal catalyst to be used at the time of
carrying out the reaction in the presence of the metal catalyst in
the production method 1 include zerovalent palladium catalysts such
as tris(dibenzylideneacetone)dipalladium (0); divalent palladium
catalysts such as palladium acetate (II) and
bis(acetonitrile)dipalladium (II); and palladium phosphine
complexes such as tetrakis(triphenylphosphine)palladium (0) and
bis(tri-tert-butylphosphine)palladium (0). As a ligand at the time
of carrying out the reaction in the presence of the ligand,
di-tert-butylphosphine or the like is used. The metal catalyst and
the ligand thereof are used at a molar ratio of normally 1:0.5 to
2, preferably 1:1, and the amount of the metal catalyst and the
ligand thereof used is in the range of 0.01 to 1 mol %, preferably
in the range of 0.1 to 0.5 mol % based on the amount of the
intermediate (2).
[0192] Examples of the base to be used at the time of carrying out
the reaction in the presence of the base in the production method 1
include salts such as potassium carbonate and potassium phosphate;
amines such as triethylamine and diisopropylethylamine; metal
hydrides such as lithium hydride and sodium hydride; metal
alkoxides such as sodium ethoxide, sodium tert-butoxide and
potassium tert-butoxide; and metal amides such as lithium amide and
lithium diisopropylamide, and one of these bases can be used alone,
or two or more thereof can be mixed at an appropriate ratio and
used. Of these, at least one of potassium phosphate, triethylamine,
diisopropylethylamine and sodium tert-butoxide is preferably used
as the base. The amount of the base used is in the range of 0.01 to
20 equivalents, preferably in the range of 0.1 to 10 equivalents,
more preferably in the range of 1 to 5 equivalents based on the
amount of the intermediate (2).
[0193] In the production method 1, the reaction temperature is in
the range of 0 to 250.degree. C., preferably 30 to 200.degree. C.,
more preferably 60 to 160.degree. C. In the production method 1,
the reaction time is in the range of 1 minute to 2 days, preferably
5 minutes to 12 hours, more preferably 10 minutes to 6 hours.
[0194] In the production method 1, substituents with which A.sup.1,
A.sup.2, A.sup.3, A.sup.4, G.sup.1, G.sup.2, G.sup.3, G.sup.4,
E.sup.1, E.sup.2, E.sup.3 and E.sup.4 are optionally substituted
may have intended substituents in the stages of the intermediate
(2) and the raw material (3). In this case, the resulting compound
(1) has intended substituents. By introducing, modifying or
converting precursor groups for intended substituents in the
intermediate (2) and/or the raw material (3) by combining a wide
range of various kinds of synthesis methods known to persons
skilled in the art, the compound (1) having intended substituents
can be produced. These synthesis methods can be arbitrarily
combined, and protection and deprotection may be appropriately
performed if necessary.
[0195] In the production method 2, the intermediate (2) and the raw
material (4) are dissolved or suspended in an appropriate solvent,
and reacted in the presence of a base to synthesize a compound of
the formula (5) (hereinafter, referred to as an "intermediate
(5)"), and the intermediate (5) and the raw material (6) are then
dissolved or suspended in an appropriate solvent, and reacted in
the presence of a base to produce a spiro compound according to the
present invention (compound (1)). While the reaction can be used in
the next step after the intermediate (5) is purified and isolated,
the reaction can be continuously carried out as a one-pot reaction.
Steps of protection, deprotection and the like can be appropriately
added if necessary.
[0196] In the production method 2, the intermediate (2) and the raw
material (4), and the intermediate (5) and the raw material (6) are
used generally at a molar ratio in the range of 1:1 to 3,
preferably at a molar ratio in the range of 1:1 to 2.
[0197] In the production method 2, examples of the solvent include
solvents which are the same as listed as solvents for the
production method 1, and of these, at least one of water, ethanol,
acetonitrile and N,N-dimethylformamide is preferably used as the
solvent.
[0198] In the production method 2, examples of the base include
bases which are the same as listed as bases for the production
method 1, of these, at least one of sodium ethoxide, triethylamine
and diisopropylethylamine is preferably used as the base. The
amount of the base used is in the range of 0.01 to 20 equivalents,
preferably in the range of 0.1 to 10 equivalents, more preferably
in the range of 1 to 5 equivalents based on the amount of the
intermediates (2) and (5).
[0199] In the production method 2, the reaction temperature is in
the range of -30 to 200.degree. C., preferably 0 to 150.degree. C.,
more preferably 20 to 120.degree. C. In the production method 2,
the reaction time is in the range of 1 minute to 2 days, preferably
5 minutes to 12 hours, more preferably 30 minutes to 6 hours.
[0200] In the production method 2, substituents with which A.sup.1,
A.sup.2, A.sup.3, A.sup.4, G.sup.1, G.sup.2, G.sup.3, G.sup.4,
E.sup.1, E.sup.2, E.sup.3 and E.sup.4 are optionally substituted
may have intended substituents in the stages of the intermediate
(2) and the raw material (6). In this case, the resulting compound
(1) has intended substituents. By introducing, modifying or
converting precursor groups for intended substituents in the
intermediate (2) and/or the raw material (6) by combining a wide
range of various kinds of synthesis methods known to persons
skilled in the art, the compound (1) having intended substituents
can be produced. These synthesis methods can be arbitrarily
combined, and protection, deprotection and the like may be
appropriately performed if necessary.
[0201] The spiro compound synthesized through the above-described
method, the intermediate, the raw material and the like may be used
in the next step in a state of a reaction solution or a crude
product, or used after being isolated through a common purification
method known to persons skilled in the art. Examples of the
purification method associated with isolation include methods
obtained by appropriately selecting or combining various types of
chromatography (column or thin-layer and normal phase or reversed
phase), distillation, sublimation, precipitation, crystallization
and centrifugation.
(Dihydroquinazolinone-Based Compound)
[0202] The nicotinamide-type tankyrase inhibitory compound
according to the present invention is preferably a compound of the
formula (II) or a pharmacologically acceptable salt thereof
(dihydroquinazolinone-based compound):
##STR00006##
[0203] where J.sub.1 and J.sub.2 each represent CH or N, with the
proviso that both J.sub.1 and J.sub.2 do not represent CH;
[0204] r represents 0 to 4;
[0205] each R.sup.101 is the same or different when r is 2 or more,
and represents a halogen atom, a C.sub.1-6 alkyl group optionally
substituted with a halogen atom, OR.sup.111, or a group represented
by the formula: --N(R.sup.112a)--R.sup.112b,
[0206] where R.sup.111, R.sup.112a and R.sup.112b are each
independently a hydrogen atom or a C.sub.1-6 alkyl group, and
[0207] s represents 0 to 5;
[0208] each R.sup.102 is the same or different when s is 2 or more,
and represents a halogen atom, a C.sub.1-6 alkyl group, OR.sup.113,
a group represented by the formula: --N(R.sup.114a)--R.sup.114b, a
group represented by the formula: --NH--C(.dbd.O)--R.sup.113, a
group represented by the formula: --C(.dbd.O)--R.sup.116, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, a nitro group, or a cyano group,
[0209] where R.sup.113 is a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, an
optionally substituted arylalkyl group, or an optionally
substituted heteroaryl group,
[0210] R.sup.114a and R.sup.114b are each independently a hydrogen
atom or a C.sub.1-6 alkyl group,
[0211] R.sup.115 is an optionally substituted alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, or a group represented by the formula:
--NH--R.sup.121,
[0212] R.sup.116 is an optionally substituted alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, OR.sup.122, or a group represented by the
formula: --N(R.sup.123a)--R.sup.123b,
[0213] R.sup.121 is an optionally substituted alkyl group, an
optionally substituted aryl group, or an optionally substituted
heteroaryl group,
[0214] R.sup.122 is a hydrogen atom, an optionally substituted
alkyl group, an optionally substituted aryl group, or an optionally
substituted heteroaryl group, and
[0215] R.sup.123a and R.sup.123b are each independently a hydrogen
atom, an optionally substituted alkyl group, an optionally
substituted aryl group, or an optionally substituted heteroaryl
group, or R.sup.123a and R.sup.123b are linked together to form a
cyclic amine;
[0216] R.sup.103 represents a hydrogen atom, a C.sub.1-6 alkyl
group, a C.sub.3-6 cycloalkyl group, or a C.sub.1-6 cycloalkyl
C.sub.1-6 alkyl group; and
[0217] R.sup.101 and R.sup.103 are optionally linked together to
form a five- to seven-membered ring hetero ring when R.sup.101 is
present at the 8-position.
[0218] When used in combination with any of anticancer agents other
than the following microtubule inhibitory compounds, more
specifically alkylating agents (e.g., temozolomide and melphalan),
antimetabolites (e.g., gemcitabine, cytarabine (Ara-C),
fluorouracil (5-FU), pemetrexed, mercaptopurine and methotrexate),
plant alkaloids (e.g., irinotecan (SN-38) and etoposide (VP-16)),
topoisomerase inhibitors (which include irinotecan (SN-38) and
etoposide (VP-16)), agents serving as both a plant alkaloid and a
topoisomerase inhibitor (e.g., irinotecan (SN-38) and etoposide
(VP-16)), anticancer antibiotics (e.g., actinomycin D,
daunorubicin, doxorubicin, bleomycin and mitoxantrone) and
platinating agents (e.g., oxaliplatin, carboplatin and cisplatin),
the dihydroquinazolinone-based compound exhibit an excellent
anticancer action without causing inhibition of each other's
anticancer action. When used in combination with any of the
following microtubule inhibitory compounds, the
dihydroquinazolinone-based compound exhibits a further excellent
synergistic anticancer action.
[0219] In the formula (11), unless otherwise specified, the number
associated with "position" indicates a position number at which RIM
is substituted in the dihydroquinazolinone-based compound, and a
position number of quinazolinone is directly applied to the
position number. Further, in the formula (11), unless otherwise
specified, the alphabet (o, m or p) associated with "position"
indicates a position number of a benzene substituent with which
R.sup.132 is substituted.
[0220] In the formula (11), the "alkyl group" is preferably a
"C.sub.1-6 alkyl group" having 1 to 6 carbon atoms, more preferably
a "C.sub.1-3 alkyl group" having 1 to 3 carbon atoms.
[0221] In the formula (11), the "aryl group" is preferably a
monocyclic ring (phenyl group) which has a binding site at any
possible position.
[0222] In the formula (11), the "heteroaryl group" is preferably
quinolyl, isoquinolyl or 1H-pyrrolo[2,3-b]pyridinyl.
[0223] In the formula (11), the "cycloalkyl group" is preferably a
monocyclic ring, more preferably a "C.sub.3-8 cycloalkyl group"
having 3 to 8 carbon atoms, still more preferably a "C.sub.3-6
cycloalkyl group" having 3 to 6 carbon atoms.
[0224] In the formula (11), the "hetero ring" is preferably a five-
to seven-membered ring, more preferably a five- or six-membered
ring, still more preferably 2,3-dihydro-1H-pyrrole,
1,2,3,4-tetrahydropyrazine or 3,4-dihydro-2H-1,4-oxazine which has
a binding site at any possible position.
[0225] In the formula (11), the "heterocycloalkyl group" is
preferably piperazinyl, pyrrolidinyl or morpholinyl which has a
binding site at any possible position.
[0226] In the formula (11), the "arylalkyl group" is preferably an
"aryl C.sub.1-6 alkyl group (aryl C.sub.1-6 alkylene group)" in
which the alkyl group has 1 to 6 carbon atoms, more preferably an
"aryl C.sub.1-3 alkyl group (aryl C.sub.1-3 alkylene group)" in
which the alkyl group has 1 to 3 carbon atoms. The "cycloalkylalkyl
group" is preferably a "cycloalkyl C.sub.1-6 alkyl group
(cycloalkyl C.sub.1-6 alkylene group)" in which the alkyl group has
1 to 6 carbon atoms, more preferably a "cycloalkyl C.sub.1-3 alkyl
group (cycloalkyl C.sub.1-3 alkylene group)" in which the alkyl
group has 1 to 3 carbon atoms, preferably a "C.sub.3-6 cycloalkyl
C.sub.1-6 alkyl group (C.sub.3-6 cycloalkyl C.sub.1-6 alkylene
group)" or "C.sub.3-6 cycloalkyl C.sub.1-3 alkyl group (C.sub.3-6
cycloalkyl C.sub.1-3 alkylene group)" in which the cycloalkyl group
has 3 to 6 carbon atoms. Further, the "heterocycloalkylalkyl group"
is preferably a "heterocycloalkyl C.sub.1-6 alkyl group
(heterocycloalkyl C.sub.1--; alkylene group)" in which the alkyl
group has 1 to 6 carbon atoms, more preferably a "heterocycloalkyl
C.sub.1-3 alkyl group (heterocycloalkyl C.sub.1-3 alkylene group)"
in which the alkyl group has 1 to 3 carbon atoms.
[0227] In the formula (11), the "cyclic amine" is preferably
pyrrolidine, piperidine, piperazine or morpholine.
[0228] In the formula (1), examples of the optional substituents
include halogen atoms (fluorine atom, chlorine atom, bromine atom
and iodine atom), a cyano group, a hydroxyl group, a thiol group, a
nitro group, C.sub.1-6 alkyl groups (preferably C.sub.1-3 alkyl
groups), aryl groups, heteroaryl groups, cycloalkyl groups
(preferably C.sub.3-6 cycloalkyl groups), heterocycloalkyl groups,
arylalkyl groups (preferably aryl C.sub.1-3 alkyl groups),
heteroarylalkyl groups (preferably heteroaryl C.sub.1-3 alkyl
groups), cycloalkylalkyl groups (preferably C.sub.3-6 cycloalkyl
C.sub.1-3 alkyl groups), heterocycloalkylalkyl groups (preferably
heterocycloalkyl C.sub.1-3 alkyl groups); groups represented by the
formula: --N(R.sup.133a)R.sup.133b [where R.sup.133a and R.sup.133b
are each independently a hydrogen atom, a C.sub.1-6 alkyl group
(preferably a C.sub.1-3 alkyl group), a cycloalkyl group
(preferably C.sub.3-6 cycloalkyl group), an aryl group, a
heteroaryl group, or a group represented by the formula:
--C(.dbd.O)--R.sup.133c [where R.sup.133c represents a C.sub.1-6
alkyl group (preferably a C.sub.1-6 alkyl group) or a cycloalkyl
group (preferably a C.sub.3-6 cycloalkyl group), an aryl group or a
heteroaryl group], or R.sup.133a and R.sup.133b are linked together
to form a four- to seven-membered ring cyclic amine]; groups
represented by the formula: --R.sup.134--C(.dbd.O)--R.sup.135
[where R.sup.134 represents a single bond, or an alkylene group
having 1 to 3 carbon atoms, and R.sup.135 represents a hydrogen
atom, a C.sub.1-6 alkyl group (preferably a C.sub.1-3 alkyl group),
a cycloalkyl group (preferably a C.sub.3-6 cycloalkyl group), an
aryl group or a heteroaryl group]; groups represented by the
formula: --R.sup.136--C(.dbd.O)--O--R.sup.137 [where R.sup.136
represents a single bond, or an alkylene group having 1 to 3 carbon
atoms, and R.sup.137 represents a hydrogen atom, a C.sub.1-6 alkyl
group (preferably a C.sub.1-3 alkyl group), a cycloalkyl group
(preferably a C.sub.1-5 cycloalkyl group), an aryl group or a
heteroaryl group]; and groups of the formula: --OR.sup.138 [where
R.sup.138 represents a C.sub.1-6 alkyl group (preferably a
C.sub.1-3 alkyl group), cycloalkyl group (preferably a C.sub.3-6
cycloalkyl group), a heterocycloalkyl group, an aryl group, a
heteroaryl group, a cycloalkylalkyl group (preferably a C.sub.3-6
cycloalkyl C.sub.1-3 alkyl group), a heterocycloalkylalkyl group
(preferably a heterocycloalkyl C.sub.1-3 alkyl group), an arylalkyl
group (preferably an aryl C.sub.1-3 alkyl group) or a
heteroarylalkyl group (preferably a heteroaryl C.sub.1-3 alkyl
group)]. Of the substituents and groups involved in formation of
the substituents, the alkyl groups, aryl groups, heteroaryl groups,
cycloalkyl groups and heterocycloalkyl groups may be further
substituted with any substituent as in the definition described
above.
[0229] In the formula (11), when the group substituted is an aryl
group or a heteroaryl group which is represented by R.sup.102, the
substituent is especially preferably a halogen atom, a cyano group,
a hydroxyl group, an optionally substituted piperazinyl group (more
preferably a piperazinyl group optionally substituted with a
C.sub.1-6 alkyl group), a piperazinyl C.sub.1-6 alkyl group such as
a piperazinylmethyl group which is optionally substituted (more
preferably a piperazinyl C.sub.1-(alkyl group such as a
piperazinylmethyl group which is optionally substituted with
C.sub.1-6 alkyl group), morpholinyl; a group represented by the
formula: --N(R.sup.133a)--R.sup.133b [where preferably, R.sup.133a
and R.sup.133b each independently represent a hydrogen atom or a
C.sub.1-3 alkyl group]; or a group represented by the formula:
--R.sup.136--C(.dbd.O)--O--R.sup.137 [where preferably, R.sup.136
represents an alkylene group having 1 to 3 carbon atoms, and
R.sup.137 represents a hydrogen atom or a C.sub.1-3 alkyl
group].
[0230] In the formula (11), when the group substituted is an
arylalkylene group represented by R.sup.113, or an alkyl group, an
aryl group or a heteroaryl group which is represented by R.sup.113
or R.sup.122, the substituent is especially preferably a halogen
atom, a hydroxyl group or a C.sub.1-3 alkyl group; a group
represented by the formula: --N(R.sup.133a)--R.sup.133b [where
preferably, R.sup.133a and R.sup.133b, each independently represent
a hydrogen atom or a C.sub.1-3 alkyl group]; or a group represented
by the formula: --OR.sup.138 [where preferably, R.sup.138
represents a C.sub.1-3 alkyl group].
[0231] Further, in the formula (11), when the group substituted is
an alkyl group, an aryl group or a heteroaryl group which is
represented by R.sup.115 or R.sup.116, the substituent is
especially preferably a halogen atom, a hydroxyl group, a
C.sub.1-3, alkyl group; a group represented by the formula:
--N(R.sup.133a)--R.sup.133b [where preferably, R.sup.133a and
R.sup.133b each independently represent a hydrogen atom or a
C.sub.1-3 alkyl group]; or a group represented by the formula:
--OR.sup.138 [where preferably, R.sup.138 represents a C.sub.1-3
alkyl group].
[0232] In the formula (11), when the group substituted is an alkyl
group, an aryl group, an arylalkylene group, a heteroaryl group
which is represented by R.sup.121, R.sup.123a or R.sup.123b, the
substituent is especially preferably a halogen atom, a hydroxyl
group, a C.sub.1-3 alkyl group; a group represented by the formula:
--N(R.sup.133a)--R.sup.133b [where preferably, R.sup.133a and
R.sup.133b each independently represent a hydrogen atom or a
C.sub.1-3_alkyl group]; or a group represented by the formula:
--OR.sup.138 [where preferably, R.sup.138 represents a C.sub.1-3
alkyl group].
[0233] In the formula (11), r represents the number of R.sup.101,
and is 0 to 4. r is preferably 0 (i.e. all the four groups
corresponding to R.sup.101 are hydrogen atoms), or 1 or 2. The
position of R.sup.101 is preferably the 7-position or the
8-position when r is 1 or 2.
[0234] In the formula (11), each R.sup.101 is the same or different
when r is 2 or more, and represents a C.sub.1-6 alkyl group
optionally substituted with a halogen atom, OR.sup.111, a group
represented by the formula: --N(R.sup.112a)--R.sup.112b. Here,
R.sup.111, R.sup.112a and --R.sup.112b are each independently a
hydrogen atom or a C.sub.1-6 alkyl group.
[0235] R.sup.101 is preferably an unsubstituted C.sub.1-6 alkyl
group; a C.sub.1-6 alkyl group substituted with a halogen atom; or
OR.sup.111 in which R.sup.111 is a hydrogen atom or a C.sub.1-3
alkyl group. More specifically, R.sup.101 is more preferably a
methyl group, an ethyl group, a hydroxyl group or a trifluoromethyl
group.
[0236] In the formula (11), s represents the number of R.sup.102,
and is 0 to 5. s is preferably 0 (i.e. all the five groups
corresponding to R.sup.102 are hydrogen atoms), or 1 to 3. The
position of R.sup.102 is preferably the m-position and/or the
p-position when r is 1 to 3. The position of R.sup.102 is
preferably the p-position when r is 1.
[0237] In the formula (11), each R.sup.102 is the same or different
when s is 2 or more, and represents a halogen atom, OR.sup.113, a
group represented by the formula: --N(R.sup.114a)--R.sup.114b, a
group represented by the formula: --NH--C(.dbd.O)--R.sup.115, a
group represented by the formula: --C(.dbd.O)--R.sup.116, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, a nitro group or a cyano group.
[0238] Here, R.sup.113 is a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, an
optionally substituted arylalkyl group, or an optionally
substituted heteroaryl group; R.sup.114a and R.sup.114b are each
independently a hydrogen atom or a C.sub.1-6 alkyl group; R.sup.115
is an optionally substituted alkyl group, an optionally substituted
aryl group, an optionally substituted heteroaryl group, or a group
represented by the formula: --NH--R.sup.121; and R.sup.116 is an
optionally substituted alkyl group, an optionally substituted aryl
group, an optionally substituted heteroaryl group, OR.sup.122, or a
group represented by the formula: --N(R.sup.123a)--R.sup.123b.
[0239] Further, R.sup.121 is an optionally substituted alkyl group,
an optionally substituted aryl group, or an optionally substituted
heteroaryl group; R.sup.122 is a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, or
an optionally substituted heteroaryl group; and R.sup.123a and
R.sup.123b are each independently a hydrogen atom, an optionally
substituted alkyl group, an optionally substituted aryl group, or
an optionally substituted heteroaryl group, or R.sup.123a and
R.sup.123b are linked together to form a cyclic amine.
[0240] R.sup.102 is preferably a halogen atom; OR.sup.113 in which
R.sup.113 is an optionally substituted alkyl group, an optionally
substituted aryl group or an optionally substituted arylalkyl
group; a group represented by the formula:
--N(R.sup.114a)--R.sup.114b in which R.sup.114a and R.sup.114b are
each independently a hydrogen atom or a C.sub.1-3 alkyl group; a
group represented by the formula: --C(.dbd.O)--R.sup.116 in which
R.sup.116 is OR.sup.122; an optionally substituted aryl group; an
optionally substituted heteroaryl group; a nitro group; or a cyano
group, preferably a halogen atom; OR.sup.113 in which R.sup.113 is
an optionally substituted alkyl group; an optionally substituted
aryl group; an optionally substituted heteroaryl group. More
specifically, R.sup.102 is more preferably a halogen atom; a
methoxy group; an ethoxy group; or a phenyl group optionally
substituted with a hydroxyl group, a 4-methylpiperazin-1-yl group,
a (4-methylpiperazin-1-yl)methyl group, a 4-morpholin-4-yl group or
a dimethylamino group.
[0241] In the formula (II), R.sup.103 is a hydrogen atom, a
C.sub.1-6 alkyl group, a C.sub.3-6 cycloalkyl group, or a C.sub.3-6
cycloalkyl C.sub.1-6 alkyl group.
[0242] R.sup.103 is preferably a hydrogen atom, a C.sub.1-3 alkyl
group, C.sub.3-6 cycloalkyl C.sub.1-3 alkyl group. More
specifically, R.sup.103 is more preferably a hydrogen atom, a
methyl group, or a cyclopropylmethyl group.
[0243] In the formula (II), when R.sup.101 is present at the
8-position, R.sup.101 and R.sup.103 present at the 1-position are
optionally linked together to form a five- to seven-membered ring
hetero ring. The five- to seven-membered ring hetero ring is
preferably pyrrolidinyl, piperidinyl or morpholinyl, more
preferably pyrrolidinyl or morpholinyl.
[0244] Examples of preferred aspects of compounds of the formula
(11) according to the present invention include, but are not
limited to, the following aspects (I) to (III), and combinations of
two or three of the aspects.
[0245] (I) A compound of the above formula (11) in which r is O or
r is 1, R.sup.101 is present at the 7-position or the 8-position,
and R.sup.101-- represents a C.sub.1-3 alkyl group optionally
substituted with a halogen atom, or a hydroxy group, or r is 1,
R.sup.101 is present at the 8-position, and R.sup.101 and R.sup.103
are linked together to form a five- or six-membered ring hetero
ring.
[0246] (II) A compound of the above formula (11) in which R.sup.103
represents a hydrogen atom, a C.sub.1-6 alkyl group or a C.sub.3-6
cycloalkyl C.sub.1-3 alkyl group, or r is 1, R.sup.101 is present
at the 8-position, and R.sup.101 and R.sup.103 are linked together
to form a five- or six-membered ring hetero ring.
[0247] (III) A compound of the above formula (11) in which s is O
or S is 1, and R.sup.102 is a halogen atom; OR.sup.113 in which
R.sup.113 is an optionally substituted C.sub.1-3 alkyl group; or an
optionally substituted aryl group.
[0248] The compounds of the above formula (11) or pharmacologically
acceptable salts thereof (dihydroquinazolinone-based compounds) can
be produced through the methods shown below. The method for
producing a dihydroquinazolinone-based compound according to the
present invention is not limited to the methods shown below, and a
range of the compounds according to the present invention is not
limited to compounds produced by the following production
methods.
[0249] Examples of the compounds of the formula (11) according to
the present invention include compounds of the above formula (11)
in which each of J.sup.1 and J.sup.2 is N. Examples thereof include
compounds in which r is 1, R.sup.101 is present at the 8-position,
and R.sup.103 is a hydrogen atom; and compounds in which r is 1,
R.sup.101 is present at the 8-position, and R.sup.101 and R.sup.103
are linked together to form a five- or six-membered ring hetero
ring.
[0250] The method for producing a dihydroquinazolinone-based
compound according to the present invention can be carried out by
combining a wide range of various kinds of synthesis methods known
to persons skilled in the art, methods obtained by making a
modification or the like to the synthesis methods if necessary, and
the like while using starting raw materials, precursors, reagents
and solvents which are commercially available or can be synthesized
through methods known to persons skilled in the art. The optional
substituents, reaction apparatus, and cooling and heating are as
described for the methods for producing a spiro compound.
[0251] The dihydroquinazolinone-based compound according to the
present invention can be prepared through, for example, the
following production method 3.
##STR00007##
[0252] In the above formulae (12) and (13), J.sup.1, J.sup.2, r,
R.sup.101, s, R.sup.102 and R.sup.103 are each independently the
same as J.sup.1, J.sup.2, r, R.sup.101, s, R.sup.102 and R.sup.103,
respectively, in the above formula (11).
[0253] The compound of the formula (12) (hereinafter, referred to
as a "raw material (12)" and the compound of the formula (13)
(hereinafter, referred to as a "raw material (13)" in the
production method 3 can be obtained as commercially available
reagents, or can be synthesized through known methods or methods
based on the known methods.
[0254] In the production method 3, the raw material (12) and the
raw material (13) are dissolved or suspended in an appropriate
solvent, and reacted in the presence or non-presence of an acid
catalyst to produce a dihydroquinazolinone-based compound according
to the present invention (a compound of the formula (11) or a salt
thereof; hereinafter, sometimes referred to as a "compound
(11)").
[0255] In the production method 3, the raw material (12) and the
raw material (13) are used generally at a molar ratio in the range
of 1:1 to 3, preferably at a molar ratio in the range of 1:1 to
1.2.
[0256] Examples of the solvent to be used in the production method
3 include protic solvents such as water, methanol, ethanol,
n-propanol, 2-propanol, n-butanol, 2-butanol and tert-butyl
alcohol; hydrocarbon-based solvents such as petroleum ether,
n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene and
xylene; halogen-based solvents such as carbon tetrachloride,
dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene and
trifluoromethylbenzene; ether-based solvents such as diethyl ether,
diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl
ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane and diphenyl ether; ester-based solvents such
as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl
acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate,
benzyl acetate, methyl propionate, ethyl propionate, n-propyl
propionate, isopropyl propionate, n-butyl propionate, isobutyl
propionate and tert-butyl propionate; and aprotic polar solvents
such as acetone, 2-butanone, methylisobutylketone, cyclohexanone,
acetonitrile, propionitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, dimethyl sulfoxide and
N-methyl-2-pyrrolidone. One of these solvents can be used alone, or
two or more thereof can be mixed at an appropriate ratio and used.
Of these, at least one of methanol, ethanol, n-propanol and
N,N-dimethylformamide is preferably used as the solvent.
[0257] Examples of the acid to be used at the time of carrying out
the reaction in the presence of the acid catalyst in the production
method 3 include mineral acids such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid
and nitric acid; carboxylic acids such as formic acid, acetic acid,
propionic acid and trifluoroacetic acid; and Lewis acids such as
boron trifluoride-diethyl ether complexes, boron trichloride, boron
tribromide, zinc chloride, stannic chloride, ferric chloride,
aluminum chloride, titanium tetrachloride and zirconium
tetrachloride. Of these, at least one of hydrochloric acid, formic
acid, acetic acid and propionic acid is preferable, with acetic
acid being more preferable, as the acid. The amount of the acid
used is in the range of 0.01 to 20 equivalents, preferably in the
range of 0.05 to 5 equivalents, more preferably in the range of 0.1
to 1 equivalents, or in the range of 0.01 to 20 equivalents,
preferably in the range of 0.1 to 10 equivalents, more preferably 1
to 5 equivalents, based on the amount of the raw material (12).
[0258] In the production method 3, the reaction temperature is in
the range of 0 to 250.degree. C., preferably 30 to 200.degree. C.,
more preferably 60 to 160.degree. C. In the production method 3,
the reaction time is in the range of 1 minute to 2 days, preferably
5 minutes to 12 hours, more preferably 10 minutes to 6 hours.
[0259] In the production method 3, optional substituents with which
R.sup.102 is substituted may have intended substituents in the
stage of the raw material (13). In this case, the resulting
compound (11) has intended substituents. By introducing, modifying
or converting precursor groups for intended substituents in the raw
material (13) by combining a wide range of various kinds of
synthesis methods known to persons skilled in the art, the compound
(11) having intended substituents can be produced. These synthesis
methods can be arbitrarily combined, and protection, deprotection
and the like may be appropriately performed if necessary.
[0260] The raw material (13) according to the production method 3
can also be produced by, for example, methods shown in the
following schemes 1 and 2.
##STR00008##
[0261] In the above formulae (14), (15) and (13-1), s and R.sup.102
are each independently the same as s and R.sup.102 in the above
formula (11).
[0262] The compound of the formula (14) (hereinafter, referred to
as a "raw material (14)") in the scheme 1 can be obtained as a
commercially available reagent, or can be synthesized through a
known method or a method based on the known method.
[0263] The compound of the formula (13-1) (hereinafter, referred to
as a "raw material (13-1)") in the scheme 1 is a type of raw
material (13). By using a known method such as the method described
in Synthesis, 1998, 10, 1140, the raw material (13-1) can be
produced from the compound of the formula (15) (compound (15))
which can be synthesized through a condensation reaction of the raw
material (14) and semicarbazide hydrochloride. A series of all
these synthesis methods are based on methodologies extensively
described in general documents of organic chemistry, and the
syntheses can be performed through the described methods themselves
or modifications thereof.
##STR00009##
[0264] In the above formulae (16), (17), (18), (19) and (13-2), s
and R.sup.102 are each independently the same as s and R.sup.102 in
the above formula (11).
[0265] The compound of the formula (16) (hereinafter, referred to
as a "raw material (16)") and the compound of the formula (19)
(hereinafter, referred to as a "raw material (19)") in the scheme 2
can be obtained as commercially available reagents, or can be
synthesized through known method or methods based on the known
methods.
[0266] The compound of the formula (13-2) (hereinafter, referred to
as a "raw material (13-2)" in the scheme 2 is a type of raw
material (13). The raw material (13-2) can be synthesized by adding
sodium azide to the compound of the formula (18) (compound (18))
(step C: Tetrahedron Letters, 2001, 42, 9117.), and the compound
(18) can be synthesized in two steps (step A and step B) from the
raw material (16) or in one step (step D) from the raw material
(19) (steps A and B: method described in Bioorganic & Medicinal
Chemistry Letters, 2008, 184932., etc.; and step D: method
described in Tetrahedron Letters, 2001, 42, 9117.). A series of all
these synthesis methods are based on methodologies extensively
described in general documents of organic chemistry, and the
syntheses can be performed through the described methods themselves
or modifications thereof.
[0267] The dihydroquinazolinone-based compound synthesized through
the above-described method, the intermediate, the raw material and
the like may be used in the next step in a state of a reaction
solution or a crude product, or used after being isolated through a
common purification method known to persons skilled in the art.
Examples of the purification method associated with isolation
include methods obtained by appropriately selecting or combining
various types of chromatography (column or thin-layer and normal
phase or reversed phase chromatography; gel permeation
chromatography (GPC) and the like), distillation, sublimation,
precipitation, crystallization and centrifugation.
[0268] As the nicotinamide-type tankyrase inhibitory compound
according to the present invention, a compound such as G-631 can
also be used.
[0269] Examples of the adenosine-type tankyrase inhibitory compound
include the compounds disclosed in Patent Literature 3 and
pharmacologically acceptable salts thereof (hereinafter, sometimes
referred to as a "triazole derivative"), IWR-1, WIKI4 and JW55, and
one of these compounds may be used alone, or two or more thereof
may be used in combination.
(Triazole Derivative)
[0270] The adenosine-type tankyrase inhibitory compound according
to the present invention is preferably at least one of a compound
of the formula (I) or a compound of the formula (II) as disclosed
in Patent Literature 3, an isomer thereof and a pharmacologically
acceptable salt thereof (triazole derivatives). The triazole
derivative is more preferably at least one of a compound of the
formula (Ia), a compound of the formula (IIb), a compound of the
formula (IIc) and a compound of the formula (IId) as disclosed in
Patent Literature 3, an isomer thereof and a pharmacologically
acceptable salt thereof. Examples of the triazole derivatives
include compounds of the following formula which are also known as
"G007-LK".
##STR00010##
[0271] The triazole derivative can be produced by using the methods
disclosed in Patent Literature 3 or by combining a wide range of
various kinds of synthesis methods known to persons skilled in the
art, methods obtained by making a modification or the like to the
synthesis methods if necessary, and the like while using starting
raw materials, precursors, reagents and solvents which are
commercially available or can be synthesized through methods known
to persons skilled in the art.
[0272] Examples of the dual-type tankyrase inhibitory compound
include NVP-TNKS656 disclosed in Non Patent Literature 2.
[0273] The dual-type tankyrase inhibitory compound can be produced
by combining a wide range of various kinds of synthesis methods
known to persons skilled in the art, methods obtained by making a
modification or the like to the synthesis methods if necessary, and
the like while using starting raw materials, precursors, reagents
and solvents which are commercially available or can be synthesized
through methods known to persons skilled in the art.
<Microtubule Inhibitory Compound>
[0274] In the present invention, the microtubule inhibitory
compound is a compound which has microtubule inhibitory activity
and which is present as an active ingredient of a microtubule
inhibitor that exhibits an antitumor effect by acting on
microtubules playing important roles in maintenance of normal
functions of cells, such as formation of a spindle in cell
division, and arrangement of intracellular organelles and
transportation of substances to the organs. The microtubule
inhibitor is also referred to as a microtubule inhibitory drug, an
anti-microtubule agent, a microtubule-targeted agent, a microtubule
inhibition activator, a microtubule-directed agent, a
microtubule-targeted and directed agent, a microtubule toxin, an
agent to perturb the microtubule function, an ingredient which acts
on microtubules, a microtubule-acting anticancer drug, or a
medicament which inhibits microtubule functions. The microtubule
inhibitors include microtubule polymerization inhibitors,
microtubule depolymerization inhibitors, microtubule formation
inhibitors, microtubule instability promoting agents, microtubule
destabilizing agents, microtubule disrupting drugs, microtubule
disintegrating drugs, microtubule dissociating agents, molecules
which promote degradation of microtubules, and compounds which
inhibit or disrupt polymerization of microtubules.
[0275] The microtubule inhibitory compound according to the present
invention may be a microtubule depolymerization inhibitor which
promotes polymerization of tubulins to stabilize and excessively
form microtubules; a microtubule polymerization inhibitor which
inhibits the polymerization; or a mixture thereof.
[0276] More specific examples of the microtubule inhibitory
compound according to the present invention include paclitaxel,
vinblastine, vincristine, vindesine, vinorelbine, docetaxel,
cabazitaxel and eribulin, and one of these compounds may be used
alone, or two or more thereof may be used in combination. The
microtubule inhibitory compound according to the present invention
may be a pharmacologically acceptable salt such as a sulfate, a
tartrate, a mesylate, an acid adduct such as an acetone adduct, or
a hydrate. As the microtubule inhibitory compound, a commercially
available product such as Taxol (paclitaxel), Exal (vinblastine),
Oncovin (vincristine sulfate), Fildesin (vindesine sulfate),
Navelbin (vinorelbine tartrate), Taxotere (docetaxel hydrate),
Onetaxotere (docetaxel hydrate), Jevtana (cabazitaxel acetone
adduct) or Halaven (eribulin mesylate) may be appropriately
used.
[0277] Of these, at least one selected from the group consisting of
docetaxel, paclitaxel, vincristine and vinblastine is more
preferable as the microtubule inhibitory compound according to the
present invention because they tend to exhibit a particularly
excellent cytocidal effect when combined with the tankyrase
inhibitory compound.
<Anticancer Agent>
[0278] Examples of cancers which are targeted by the anticancer
agent of the present invention include colorectal cancer, gastric
cancer, esophagus cancer, colon cancer, liver cancer, pancreas
cancer, breast cancer, lung cancer, gallbladder cancer, bile duct
cancer, biliary duct cancer, rectal cancer, ovary cancer, uterus
cancer, renal cancer, bladder cancer, prostate cancer,
osteosarcoma, brain cancer, leukemia, myosarcoma, skin cancer,
malignant melanoma, malignant lymphoma, tongue cancer, myeloma,
thyroid cancer, cutaneous metastatic cancer and cutaneous melanoma.
Of these, lower digestive organ cancers are preferably targeted,
and colorectal cancer is more preferably targeted.
[0279] The anticancer agent of the present invention is used in the
form of a combination of the tankyrase inhibitory compound and the
microtubule inhibitory compound. In the present invention, the
combination may take any of a form in which a tankyrase inhibitor
containing the tankyrase inhibitory compound as an active
ingredient and a microtubule inhibitor containing the microtubule
inhibitory compound as an active ingredient are simultaneously used
or administered (simultaneous separate agents); a form in which the
tankyrase inhibitor and the microtubule inhibitor are separately
used or administered (intertemporal separate agents); and a form of
a combined agent of the tankyrase inhibitor and the microtubule
inhibitor (integrated agent).
[0280] Accordingly, the present invention provides an anticancer
agent comprising a combination of the tankyrase inhibitor and the
microtubule inhibitor; an anticancer agent which is used to be
administered in combination with the microtubule inhibitor and
which contains a tankyrase inhibitory compound as an active
ingredient; an anticancer agent which is used to be administered in
combination with the tankyrase inhibitor and which contains a
microtubule inhibitory compound as an active ingredient; an
anticancer agent in which a tankyrase inhibitory compound and a
microtubule inhibitory compound are blended as active ingredients;
and a kit including the tankyrase inhibitor and the microtubule
inhibitor.
[0281] The tankyrase inhibitor, the microtubule inhibitor and the
anticancer agent according to the present invention may each
independently further contain other therapeutic agents. The other
therapeutic agents may be simultaneously or intertemporally used in
combination. Examples of the other therapeutic agents include other
anticancer agents (antiproliferative agents, antineoplastic agents,
DNA-damaging agents and combinations thereof), more specifically
the above-described alkylating agents, antimetabolites, plant
alkaloids, anticancer antibiotics, platinating agents; mitosis
inhibitors; topoisomerase inhibitors; agents serving as both a
plant alkaloid and a topoisomerase inhibitor; cell division
inhibitors; growth factor function inhibitors such as EGFR
antibodies; angiogenesis inhibition agonists such as VEGF
antibodies and VEGFR antibodies; cancer cell metastasis suppression
agonists such as metalloprotease inhibitors; antisense therapeutic
drugs such as Ras antisense; and immunotherapeutic drugs with
anti-PD-1 antibodies and T-cells. One of these therapeutic agents
may be used alone, or two or more thereof may be used in
combination.
[0282] The tankyrase inhibitor, the microtubule inhibitor and the
anticancer agent according to the present invention may be
administered through any of oral and parenteral administration
routs such as routs of inhalation administration, nasal
administration, ophthalmic administration, subcutaneous
administration, intravenous administration, intramuscular
administration, rectal administration and transdermal
administration, and can be administered to humans or animals other
than humans. Therefore, the tankyrase inhibitor, the microtubule
inhibitor and the anticancer agent according to the present
invention may each independently take an appropriate dosage form
depending on an administration route.
[0283] Examples of the tankyrase inhibitor, the microtubule
inhibitor and the anticancer agent according to the present
invention each independently include oral agents such as tablets,
pills, capsules, granules, powders, fine granules, troches,
elixirs, suspensions, emulsions and syrups; solutions for external
use such as inhalations, nasal solutions and ophthalmic solutions;
injections such as intravenous injections and intramuscular
injections; and parenteral agents such as rectal administration
agents, suppositories, lotions, sprays, ointments, creams and
patches.
[0284] The tankyrase inhibitor, the microtubule inhibitor and the
anticancer agent according to the present invention may further
contain, depending on the dosage form, excipients such as diluents,
extenders, humectants, surfactants, disintegrants, binders,
lubricating agents, dispersants, buffering agents, preservatives,
solubilizing agents, antiseptics, correctives, soothing agents,
stabilizers, lubricants and colorants which are commonly used in
the area of pharmaceuticals. Production can be performed through
conventional methods using these additives. Examples of the
additives include lactose, fructose, glucose, starch, gelatin,
magnesium carbonate, synthetic magnesium silicate, talc, magnesium
stearate, methylcellulose, carboxymethylcellulose or salts thereof,
gum arabic, olive oil, propylene glycol, polyethylene glycol,
syrup, vaseline, glycerin, ethanol, citric acid, sodium chloride,
sodium sulfite and sodium phosphate.
[0285] In the tankyrase inhibitor and the anticancer agent
containing the tankyrase inhibitory compound according to the
present invention, the content of the tankyrase inhibitory compound
according to the present invention (the total content of tankyrase
inhibitory compounds in the case of a mixture; the same applies
hereinbelow) is appropriately adjusted depending on a dosage form
of the agent, and therefore may vary, and the content of the
tankyrase inhibitory compound is typically 0.01 to 70 mass %,
preferably 0.05 to 50 mass %, in terms of a free form, based on the
total mass of the tankyrase inhibitor or the anticancer agent. The
dosage of the tankyrase inhibitory compound according to the
present invention is appropriately adjusted depending on an
individual case with consideration given to the dose regimen and
the age, the body weight, the sex, the type of disease and the
severity of a symptom of a patient, and the like, and therefore may
vary, and the dosage of the tankyrase inhibitory compound is
typically 0.1 to 2,000 mg, preferably 1 to 1,000 mg, per day per
adult. This amount of the tankyrase inhibitory compound is
administered once or in several divided doses a day.
[0286] In the microtubule inhibitor and the anticancer agent
containing the microtubule inhibitory compound according to the
present invention, the content of the microtubule inhibitory
compound according to the present invention (the total content of
microtubule inhibitory compounds in the case of a mixture; the same
applies hereinbelow) is appropriately adjusted depending on a
dosage form of the agent, and therefore may vary, and the content
of the microtubule inhibitory compound is typically 0.01 to 70 mass
%, preferably 0.05 to 50 mass %, in terms of a free form, based on
the total mass of the microtubule inhibitor or the anticancer
agent. The dosage of the microtubule inhibitory compound according
to the present invention is appropriately adjusted depending on an
individual case with consideration given to the dose regimen and
the age, the body weight, the sex, the type of disease and the
severity of a symptom of a patient, and the like, and therefore may
vary, and the dosage of the microtubule inhibitory compound is
typically 0.1 to 2,000 mg, preferably 1 to 1,000 mg, per day per
adult. This amount of the microtubule inhibitory compound is
administered once or in several divided doses a day.
[0287] In the anticancer agent containing the tankyrase inhibitory
compound and the microtubule inhibitory compound (integrated agent)
according to the present invention, the mass ratio of the content
of the tankyrase inhibitory compound and the content of the
microtubule inhibitory compound (tankyrase inhibitory compound
microtubule inhibitory compound) is appropriately adjusted, and
therefore may vary, and the mass ratio of the contents of the
compounds is, for example, 1:20,000 to 20,000:1, preferably 1:1,000
to 1,000 to 1, more preferably 1:100 to 100:1 in terms of a free
form.
[0288] When the tankyrase inhibitory compound and the microtubule
inhibitory compound according to the present invention are used as
separate agents, the mass ratio of the dosage of the tankyrase
inhibitory compound and the dosage of the microtubule inhibitory
compound (tankyrase inhibitory compound:microtubule inhibitory
compound) is appropriately adjusted, and therefore may vary, and
the mass ratio of the dosages of the compounds is, for example,
1:20,000 to 20,000:1, preferably 1:1,000 to 1,000 to 1, more
preferably 1:100 to 100:1 in terms of a free form.
[0289] The integrated agent can be used in combination with the
separate agents, and the integrated agent and/or the separate
agents can be used in combination with single agents of the
tankyrase inhibitor and/or the microtubule inhibitor. For example,
an agent for intravenous injection prepared as the integrated agent
may be infused first one or several times, followed by orally
administrating only the tankyrase inhibitor for several days.
EXAMPLES
[0290] Hereinafter, the present invention will be described in more
detail on the basis of Examples, which should not be construed as
limiting the scope of the present invention. Various applications,
changes, modifications and the like can be made without departing
from the scope of the present invention. Further, methods for
producing compounds used in Examples will be described in Compound
Examples, which are examples shown for explaining implementation of
the present invention in detail, and are should not be construed as
limiting the scope of the present invention. Various applications,
changes, modifications and the like can be made without departing
from the scope of the present invention.
[0291] Abbreviations used in Examples and Compound Examples below
have the following meanings.
M: mol/L .sup.1H-NMR: proton nuclear magnetic resonance spectrum
(270 MHz, 400 MHz or 500 MHz) MS (ESI): mass spectrum (electrospray
ionization method) DMSO: dimethyl sulfoxide BzI and Bn: benzyl MPM:
4-methoxyphenylmethyl, 4-methoxybenzyl TBS: tert-butyldimethylsilyl
Cbz: benzyloxycarbonyl Boc: tert-butyloxycarbonyl Ts:
para-toluenesulfonyl
Compound Example 1
2-(4,6-Difluoro-1-(2-hydroxyethyl)spiro[indolin-3,4'-piperidin]-1'-yl)-5,6-
,7,8-tetrahydroquinazolin-4(3H)-one
a)
1'-Benzyloxycarbonyl-1-tert-butyloxycarbonyl-4,6-difluorospiro[indolin--
3,4'-piperidine]
##STR00011##
[0293] 278.9 mg of 1-benzyloxycarbonyl-4-formylpiperidine was
dissolved in 5 ml of chloroform, 244.4 mg of
3,5-difluorophenylhydrazine hydrochloride and 0.26 ml of
trifluoroacetic acid were added, the mixture was stirred under
heating and reflux for 1 hour, 358.5 mg of sodium
triacetoxyborohydride was then added, and the mixture was stirred
at room temperature for 1 hour. To the reaction mixture was added a
saturated sodium hydrogencarbonate aqueous solution, and the
mixture was extracted with chloroform. The extract was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, the residue thus obtained was dissolved in 5 ml of
chloroform, 295.4 mg of di-tert-butyl decarbonate and 165.4 mg of
dimethylaminopyridine were added, and the mixture was stirred at
room temperature for 1 hour. To the reaction mixture was added a
saturated sodium hydrogencarbonate aqueous solution, and the
mixture was extracted with chloroform. The extract was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, and the residue thus obtained was purified by silica gel
chromatography (hexane/ethyl acetate=80/20) to give 82.8 mg of the
title compound.
[0294] MS(ESI) m/z: 459 [M+H].sup.+
b)
2-(1-tert-Butyloxycarbonyl-4,6-difluorospiro[indolin-3,4'-piperidin]-1'-
-yl)-5,6,7,8-tetrahydroquinazolin-4 (3H)-one
##STR00012##
[0296] 275.6 mg of
1'-benzyloxycarbonyl-1-tert-butyloxycarbonyl-4,6-difluorospiro[indolin-3,-
4'-piperidine] was dissolved in 3 ml of methanol, 64.0 mg of 10%
palladium carbon and 189.5 mg of ammonium formate were added, and
the mixture was heated and refluxed for 1 hour. The reaction
solution was filtered through Celite, and the filtrate was
concentrated under reduced pressure. The residue thus obtained was
dissolved in 3 ml of acetonitrile, 105.7 mg of 1-amidinopyrazole
hydrochloride and 0.251 ml of triethylamine were added, and the
mixture was stirred at room temperature for 1 hour. The reaction
mixture was concentrated, the residue thus obtained was dissolved
in 5 ml of ethanol, 0.12 ml of ethyl 2-oxocyclohexanecarboxylate
and 0.58 ml of a 21% sodium ethoxide ethanol solution were added,
and the mixture was stirred under heating and reflux for 3 hours.
To the reaction mixture was added an ammonium chloride aqueous
solution, and the mixture was extracted with chloroform. The
extract was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure, and the residue thus obtained
was purified by silica gel column chromatography
(methanol/chloroform=10/90) to give 48.5 mg of the title
compound.
[0297] MS(ESI) m/z: 473 [M+H].sup.+
c)
2-(4,6-Difluorospiro[indolin-3,4'-piperidin]-1'-yl)-5,6,7,8-tetrahydroq-
uinazolin-4(3H)-one
##STR00013##
[0299] 48.5 mg of
2-(1-tert-butyloxycarbonyl-4,6-difluorospiro[indolin-3,4'-piperidin]-1'-y-
l)-5,6,7,8-tetrahydroquinazolin-4(3H)-one was dissolved in 1 ml of
chloroform, 1 ml of trifluoroacetic acid was added, and the mixture
was stirred at room temperature for 1 hour. To the reaction mixture
was added a saturated sodium hydrogencarbonate aqueous solution,
and the mixture was extracted with chloroform. The extract was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure, and the residue thus obtained was purified by
silica gel column chromatography (chloroform/methanol=90/10) to
give 2.0 mg of the title compound.
[0300] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.66-1.78 (m,
6H), 1.80-1.86 (m, 2H), 2.19-2.28 (m, 2H), 2.36-2.41 (m, 2H),
2.45-2.50 (m, 2H), 2.93-3.02 (m, 2H), 3.60 (s, 2H), 3.98 (br.s,
1H), 4.32-4.39 (m, 2H), 6.07-6.14 (m, 2H), 10.71 (br.s, 1H).
[0301] MS (ESI) m/z: 373 [M+H].sup.+.
d)
2-(4,6-Difluoro-1-(2-hydroxyethyl)spiro[indolin-3,4'-piperidin]-1'-yl)--
5,6,7,8-tetrahydroquinazolin-4 (3H)-one
##STR00014##
[0303] 31.8 mg of
2-(4,6-difluorospiro[indolin-3,4'-piperidin]-1'-yl)-5,6,7,8-tetrahydroqui-
nazolin-4(3H)-one was dissolved in chloroform, 15.4 mg of a
glycolaldehyde dimer, 54.3 mg of sodium triacetoxyborohydride and
acetic acid were added, and the mixture was stirred at room
temperature for 14 hours. To the reaction mixture, a saturated
sodium hydrogencarbonate aqueous solution was added, and the
mixture was extracted with chloroform. The extract was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, and the residue thus obtained was purified by silica gel
column chromatography (methanol/chloroform=10/90) to give 12.4 mg
of the title compound.
[0304] 1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.64-1.83 (m, 6H),
2.20-2.30 (m, 2H), 2.33-2.38 (m, 2H), 2.45-2.50 (m, 2H), 2.91-3.00
(m, 2H), 3.30 (t, J=5.4 Hz, 2H), 3.54 (s, 2H), 3.84 (t, J=5.4 Hz,
2H), 4.42-4.49 (m, 2H), 6.00-6.09 (m, 2H), 11.69 (br.s, 1H).
[0305] MS (ESI) m/z: 417 [M+H].sup.+.
Compound Example 5
4-Fluoro-1-methyl-1'-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyr-
imidin-2-yl)-6-(4-methylpiperazin-1-yl)spiro[indolin-3,4'-piperidin]-2-one
a) tert-Butyl 2-cyano-2-(2,6-difluoro-4-methoxyphenyl)acetate
##STR00015##
[0307] 1.1151 g of 4-bromo-3,5-difluoroanisole, 1.2013 g of sodium
tert-butoxide, 45.8 mg of tris(dibenzylideneacetone)dipalladium (0)
and 29.0 mg of tri-tert-butylphosphine tetrafluoroborate were
dissolved in 1,4-dioxane, 0.856 ml of tert-butyl cyanoacetate was
added, and the mixture was stirred under microwave irradiation at
180.degree. C. for 30 minutes. Water was added to the reaction
mixture, the mixture was filtered through Celite, and the filtrate
was extracted with ethyl acetate. The extract was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, and the residue thus obtained was purified by silica gel
column chromatography (ethyl acetate/hexane=20/80) to give 1.2791 g
of the title compound.
[0308] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.50 (s, 9H),
3.81 (s, 3H), 4.92 (br.s, 1H), 6.50-6.55 (m, 2H).
[0309] MS (ESI) m/z: 284 [M+H].sup.+.
b) 2-(2,6-Difluoro-4-methoxyphenyl) acetonitrile
##STR00016##
[0311] 1.2791 g of tert-butyl
2-cyano-2-(2,6-difluoro-4-methoxyphenyl)acetate was dissolved in
toluene, 85.9 mg of para-toluenesulfonic acid-hydrate was added,
and the mixture was stirred under heating and reflux for 1 hour. To
the reaction mixture was added a saturated sodium hydrogencarbonate
aqueous solution, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure, and the residue thus obtained
was purified by silica gel column chromatography (ethyl
acetate/hexane=20/80) to give 698.8 mg of the title compound.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 3.64 (s, 2H), 3.80 (s,
3H), 6.48-6.54 (m, 2H).
[0312] MS (ESI) m/z: 184 [M+H].sup.+.
c) 1-(tert-Butyloxycarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)
piperidine-4-carbonitrile
##STR00017##
[0314] 698.8 mg of 2-(2,6-difluoro-4-methoxyphenyl)acetonitrile was
dissolved in N,N-dimethylformamide, 1.1086 g of
N-(tert-butyloxycarbonyl)-N,N-bis(2-chloroethyl)amine and 457.8 mg
of sodium hydride were added, and the mixture was stirred at
80.degree. C. for 3 hours. To the reaction mixture was added a
saturated ammonium chloride aqueous solution, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure, and the
residue thus obtained was purified by silica gel chromatography
(ethyl acetate/hexane=20/80) to give 881.4 mg of the title
compound.
[0315] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.48 (s, 9H),
2.11-2.20 (m, 2H), 2.30-2.36 (m, 2H), 3.17-3.29 (m, 2H), 3.79 (s,
3H), 4.10-4.27 (m, 2H), 6.46-6.51 (m, 2H).
[0316] MS (ESI) m/z: 353 [M+H].sup.+.
d)
1-(tert-Butyloxycarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-4-c-
arboxamide
##STR00018##
[0318] 2.0886 g of
1-(tert-butyloxycarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidine-4-ca-
rbonitrile was dissolved in dimethyl sulfoxide, 2.5 ml of 5 N
sodium hydroxide and 2.5 ml of a 30% hydrogen peroxide aqueous
solution were added, and the mixture was stirred at 80.degree. C.
for 14 hours. To the reaction mixture was added a saturated
ammonium chloride aqueous solution, and the mixture was extracted
with ethyl acetate. The extract was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure, and the residue
thus obtained was purified by silica gel column chromatography
(ethyl acetate/hexane=20/80) to give 2.1733 g of the title
compound.
[0319] MS(ESI) m/z: 371 [M+H].sup.+
e)
1'-(tert-Butyloxycarbonyl)-4-fluoro-6-methoxy-1-methylspiro[indolin-3,4-
'-piperidin]-2-one
##STR00019##
[0321] 2.1733 g of
1-(tert-butyloxycarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-4-car-
boxamide was dissolved in N,N-dimethylformamide, 139.9 mg of
lithium hydride was added, the mixture was stirred at 120.degree.
C. for 14 hours, 1.1 ml of iodomethane was then added, and the
mixture was stirred for 1 hour. To the reaction mixture was added a
saturated ammonium chloride aqueous solution, and the mixture was
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure, and the
residue thus obtained was purified by silica gel column
chromatography (ethyl acetate/hexane=20/80) to give 1.8156 g of the
title compound.
[0322] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.50 (s, 9H),
1.69-1.76 (m, 2H), 2.05-2.14 (m, 2H), 3.16 (s, 3H), 3.66-3.98 (m,
7H), 6.22-6.28 (m, 2H).
[0323] MS (ESI) m/z: 365 [M+H].sup.+.
f)
1'-(tert-Butyloxycarbonyl)-4-fluoro-6-hydroxy-1-methylspiro[indolin-3,4-
'-piperidin]-2-one
##STR00020##
[0325] 27.7 mg of
1'-(tert-butyloxycarbonyl)-4-fluoro-6-methoxy-1-methylspiro[indolin-3,4'--
piperidin]-2-one was dissolved in chloroform, 1.5 ml of boron
tribromide (17% dichloromethane solution, about 1 mol/l) was added,
and the mixture was stirred at room temperature for 14 hours. To
the reaction mixture were added methanol, a 5 N sodium hydroxide
aqueous solution and 0.026 ml of di-tert-butyl decarbonate, and the
mixture was stirred for 1 hour. To the reaction mixture was added a
1 N hydrochloric acid aqueous solution, and the mixture was
extracted with chloroform. The extract was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure, and the
residue thus obtained was purified by silica gel column
chromatography (ethyl acetate/hexane=50/50) to give 26.6 mg of the
title compound.
[0326] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.51 (s, 9H),
1.70-1.77 (m, 2H), 2.03-2.12 (m, 2H), 3.68-3.94 (m, 4H), 6.23-6.28
(m, 2H), 8.05 (br.s, 1H).
[0327] MS (ESI) m/z: 351 [M+H].sup.+.
g)
1'-(tert-Butyloxycarbonyl)-4-fluoro-1-methyl-2-oxospiro[indolin-3,4'-pi-
peridin]-6-yl trifluoromethanesulfonate
##STR00021##
[0329] 175.2 mg of
1'-(tert-butyloxycarbonyl)-4-fluoro-6-hydroxy-1-methylspiro[indolin-3,4'--
piperidin]-2-one was dissolved in chloroform, 0.21 ml of
triethylamine and 0.12 ml of trifluoromethanesulfonic anhydride
were added, and the mixture was stirred at room temperature for 1
hour. To the reaction mixture was added a saturated sodium
hydroxide aqueous solution, and the mixture was extracted with
chloroform. The extract was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure, and the residue thus
obtained was purified by silica gel column chromatography (ethyl
acetate/hexane=20/80) to give 159.2 mg of the title compound.
[0330] MS(ESI) m/z: 483 [M+H].sup.+
h)
4-Fluoro-1-methyl-1'-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]-
pyrimidin-2-yl)-6-(4-methylpiperazin-1-yl)spiro[indolin-3,4'-piperidin]-2--
one
##STR00022##
[0332] 48.2 mg of
1'-(tert-butyloxycarbonyl)-4-fluoro-1-methyl-2-oxospiro[indolin-3,4'-pipe-
ridin]-6-yl trifluoromethanesulfonate, 48.9 mg of cesium carbonate,
2.2 mg of palladium acetate and 12.5 mg of
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were dissolved in
toluene, 0.013 ml of N-methylpiperazine was added, and the mixture
was stirred under heating and reflux for 14 hours. The reaction
mixture was filtered through Celite, the filtrate was concentrated
under reduced pressure, and the residue thus obtained was purified
by silica gel column chromatography (methanol/chloroform=10/90).
The product thus obtained was dissolved in chloroform,
trifluoroacetic acid was added, and the mixture was stirred at room
temperature for 1 hour. To the reaction mixture was added a
saturated sodium hydroxide aqueous solution, and the mixture was
extracted with chloroform. The extract was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure, the
residue thus obtained was dissolved in ethanol, 24.0 mg of
2-chloro-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one
and 0.017 ml of triethylamine were added, and the mixture was
stirred under microwave irradiation at 150.degree. C. for 30
minutes. To the reaction mixture was added a saturated sodium
hydrogencarbonate aqueous solution, and the mixture was extracted
with chloroform. The extract was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure, and the residue
thus obtained was purified by silica gel column chromatography
(methanol/chloroform=10/90) to give 31.5 mg of the title
compound.
[0333] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.80-1.87 (m,
4H), 2.11-2.20 (m, 2H), 2.36 (s, 3H), 2.44-2.49 (m, 2H), 2.55-2.60
(m, 4H), 3.07 (s, 3H), 3.17 (s, 3H), 3.21-3.27 (m, 6H), 3.89-3.98
(m, 2H), 4.10-4.17 (m, 2H), 6.19-6.25 (m, 2H), 10.32 (br.s,
1H).
[0334] MS (ESI) m/z: 496 [M+H].sup.+.
Compound Example 19
6-(cis-2,6-Dimethylmorpholin-4-yl)-4-fluoro-1-methyl-1'-(8-methyl-4-oxo-3,-
4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indolin-3,4'-piperidi-
n]-2(1H)-one
a)
1'-(tert-Butyloxycarbonyl)-6-(cis-2,6-dimethylmorpholino)-4-fluoro-1-me-
thylspiro[indolin-3,4'-piperidin]-2-one
##STR00023##
[0336] 48.2 mg of
1'-(tert-butyloxycarbonyl)-4-fluoro-1-methyl-2-oxospiro[indolin-3,4'-pipe-
ridin]-6-yl trifluoromethanesulfonate, 48.9 mg of cesium carbonate,
2.2 mg of palladium acetate and 6.2 mg of
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were dissolved in
toluene, 0.015 ml of cis-2,6-dimethylmorpholine was added, and the
mixture was stirred under heating and reflux for 14 hours. The
reaction mixture was filtered through Celite, the filtrate was
concentrated under reduced pressure, and the residue thus obtained
was purified by silica gel column chromatography (ethyl
acetate/hexyl=50/50) to give 18.2 mg of the title compound.
[0337] 1H-NMR (400M Hz, CHCl.sub.3) .delta.: 1.27 (d, J=6.2 Hz,
6H), 1.49 (s, 9H), 1.70-1.77 (m, 2H), 2.01-2.11 (m, 2H), 2.41-2.49
(m, 2H), 3.17 (s, 3H), 3.40-3.45 (m, 2H), 3.68-3.94 (m, 6H),
6.15-6.23 (m, 2H).
[0338] MS (ESI) m/z: 448 [M+H].sup.+.
b)
6-(cis-2,6-Dimethylmorpholin-4-yl)-4-fluoro-1-methyl-1'-(8-methyl-4-oxo-
-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indolin-3,4'-piper-
idin]-2(1H)-one
##STR00024##
[0340] 29.9 mg of
1'-(tert-butyloxycarbonyl)-6-(cis-2,6-dimethylmorpholino)-4-fluoro-1-meth-
ylspiro[indolin-3,4'-piperidin]-2-one was dissolved in 1 ml of
chloroform, 1 ml of trifluoroacetic acid was added, and the mixture
was stirred at room temperature for 1 hour. To the reaction mixture
was added a saturated sodium hydroxide aqueous solution, and the
mixture was extracted with chloroform. The extract was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, the residue thus obtained was dissolved in ethanol, 16.0
mg of
2-chloro-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one
and 0.028 ml of triethylamine were added, and the mixture was
stirred under microwave irradiation at 150.degree. C. for 30
minutes. To the reaction mixture was added a saturated sodium
hydrogencarbonate aqueous solution, and the mixture was extracted
with chloroform. The extract was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure, and the residue
thus obtained was purified by silica gel column chromatography
(methanol/chloroform=10/90) to give 22.6 mg of title compound.
[0341] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.27 (d, J=6.2
Hz, 6H), 1.79-1.87 (m, 4H), 2.11-2.20 (m, 2H), 2.42-2.49 (m, 4H),
3.07 (s, 3H), 3.19 (s, 3H), 3.23-3.27 (m, 2H), 3.40-3.45 (m, 2H),
3.73-3.82 (m, 2H), 3.89-3.97 (m, 2H), 4.07-4.15 (m, 2H), 6.16-6.23
(m, 2H).
[0342] MS (ESI) m/z: 511 [M+H].sup.+.
[0343] The compounds of Compound Examples 2 to 4, 6 to 18 and 20 to
24 were prepared using the methods of Compound Examples 1, 5 and 19
and methods based thereon, and methods disclosed in literatures and
methods based thereon. Tables 1 to 7 below show the compounds of
Compound Examples 1 to 24. By X-ray diffraction described below,
the compound prepared in Compound Example 1 was confirmed to be a
nicotinamide-type compound which binds to the nicotinamide binding
pocket of tankyrase.
<X-Ray Diffraction>
[0344] X-ray diffraction data of a tankyrase-2 crystal soaked with
the compound prepared in Compound Example 1 was measured with
BL26B2 Beam Line in a large synchrotron radiation facility Spring-8
(Sayo-gun, Hyogo). The wavelength of the X-ray was 1.000 .ANG., and
MX-225 (Rayonix, LLC) was used as a detector. The diffraction data
was treated with XDS (Kabsch, 2010) and the CCP4 program (Winn et
al., 2011).
TABLE-US-00001 TABLE 1 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 1 2-[4,6-Difluoro-1-(2-
hydroxyethyl)spiro [indolin-3,4'-piperidin]- 1'-yl]-5,6,7,8-
tetrahydroquinazolin- 4(3H)-one ##STR00025## 1.64-1.83 (m, 6 H),
2.20-2.30 (m, 2 H), 2.33- 2.38 (m, 2 H), 2.45-2.50 (m, 2 H),
2.91-3.00 (m, 2 H), 3.30 (t, J = 5.4 Hz, 2 H), 3.54 (s, 2 H), 3.84
(t, J = 5.4 Hz, 2 H), 4.42- 4.49 (m, 2 H), 6.00-6.09 (m, 2 H),
11.69 (br. s, 1 H). CDCl3 417 [M + H]+ 2 4-Fluoro-1-(2-
hydroxyethyl)-6- methoxy-1'-(8- methyl-4-oxo- 3,4,5,6,7,8-
hexahydropyrido [2,3-d]pyrimidin- 2-yl)spiro [indolin-3,4'-
piperidin]-2-one ##STR00026## 1.81-1.88 (m, 4 H), 2.17-2.25 (m, 2
H), 2.47- 2.51 (m, 2 H), 3.08 (s, 3 H), 3.24-3.29 (m, 2 H), 3.80
(s, 3 H), 3.83-3.93 (m, 6 H), 4.06- 4.13 (m, 2 H), 6.26 (dd, J =
11.6, 2.1, 1 H), 6.34 (d, J = 2.1, 1 H). CDCl3 458 [M + H]+ 3
2-(4,6-Difluoro-1'- (8-methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)-2-oxospiro [indolin-3,4'- piperidin]-1-yl)
acetonitrile ##STR00027## 1.80-1.87 (m, 4 H), 2.26-2.34 (m, 2 H),
2.43- 2.47 (m, 2 H), 3.07 (s, 3 H), 3.23-3.27 (m, 2 H), 3.76-3.85
(m, 2 H), 4.30- 4.37 (m, 2 H), 4.63 (s, 2 H), 6.56-6.62 (m, 2 H),
11.11 (br.s, 1 H). CDCl3 441 [M + H]+ 4 2-[4-Fluoro-6-
methoxy-1'-(8- methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)-2-oxospiro [indolin-3,4'- piperidin]-1-yl]
acetonitrile ##STR00028## 1.80-1.87 (m, 4 H), 2.21-2.30 (m, 2 H),
2.43- 2.48 (m, 2 H), 3.07 (s, 3 H), 3.23-3.27 (m, 2 H), 3.78-3.87
(m, 5 H), 4.23- 4.30 (m, 2 H), 4.61 (s, 2 H), 6.35 (dd, J = 11.6,
2.0 Hz, 1 H), 6.39 (d, J = 2.1 Hz, 1 H), CDCl3 453 [M + H]+ 10.84
(br.s, 1 H).
TABLE-US-00002 TABLE 2 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 5 4-Fluoro-1-methyl-
1'-(8-methyl-4- oxo-3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin-
2-yl)-6-(4- methylpiperazin- 1-yl)spiro [indolin-3,4'-
piperidin]-2-one ##STR00029## 1.80-1.87 (m, 4 H), 2.11-2.20 (m, 2
H), 2.36 (s, 3 H), 2.44- 2.49 (m, 2 H), 2.55-2.60 (m, 4 H), 3.07
(s, 3 H), 3.17 (s, 3 H), 3.21-3.27 (m, 6 H), 3.89-3.98 (m, 2 H),
4.10-4.17 (m, 2 H), 6.19-6.25 (m, 2 H), 10.32 (br s, 1 H). CDCl3
496 [M + H]+ 6 4-Fluoro-1-methyl- 1'-(8-methyl-4- oxo-3,4,5,6,7,8-
hexahydropyrido [2,3-d]pyrimidin- 2-yl)-6-(oxetan-3-
ylmethoxy)spiro [indolin-3,4'- piperidin]-2-one ##STR00030##
1.79-1.86 (m, 4 H), 2.15-2.24 (m, 2 H), 2.43-2.48 (m, 2 H), 3.07
(s, 3 H), 3.17 (s, 3 H), 3.22-3.27 (m, 2 H), 3.40-3.47 (m, 1 H),
3.88-3.97 (m, 2 H), 4.17-4.24 (m, 4 H), 4.54-4.58 (m, 2 H),
4.87-4.92 (m, 2 H), 6.25-6.30 (m, 2 H), 10.76 (br. CDCl3 484 [M +
H]+ s, 1 H). 7 4-Fluoro-1-methyl- 1'-(8-methyl-4- oxo-3,4,5,6,7,8-
hexahydropyrido [3,3-d]pyrimidin- 2-yl)-6- [(tetrahydro-2H-
pyran-4-yl)oxy] spiro[indolin- 3,4'-piperidin]- 2-one ##STR00031##
1.75-1.86 (m, 6 H), 1.99-2.07 (m, 2 H), 2.15-2.24 (m, 2 H),
2.43-2.48 (m, 2 H), 3.07 (s, 3 H), 3.17 (s, 3 H), 3.22-3.27 (m, 2
H), 3.56-3.63 (m, 2 H), 3.88-4.01 (m, 4 H), 4.16-4.23 (m, 2 H),
4.43-4.49 (m, 1 H), 6.24-6.28 (m, 2 H), 10.63 (br. CDCl3 498 [M +
H]+ s, 1 H).
TABLE-US-00003 TABLE 3 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 8 4-Fluoro-1'-(8-
methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin-
2-yl)-6-[2-(4- methylpiparazin- 1-yl)ethoxy]-1- (2,2,2-
trifluoroethyl) spiro[indolin- ##STR00032## 1 78-1.87 (m, 4 H),
2.21-2.32 (m, 5 H), 2.41-2.68 (m, 10 H), 2.81 (t, J = 5.8 Hz, 2 H),
3.06 (s, 3 H), 3.22-3.27 (m, 2 H), 3.80-3.89 (m, 2 H), 4.08 (t, J =
5.8 Hz, 2 H), 4.22-4.33 (m, 4 H), 6.29-6.36 (m, 2 H). CDCl3 608 [M
+ H]+ 3,4'-piperidin]- 2(1H)-one 9 {[4-Fluoro-1'- (8-methyl-4-
oxo-3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin- 2-yl)-2-oxo-1-
(2,2,2- trifluoroethyl) spiro[indolin- 3,4'-piperidin]-
6-yl]oxy}acetic acid ##STR00033## 1.71-1.81 (m, 4 H), 1.98-2.08 (m,
2 H), 2.29-2.35 (m, 2 H), 3.00 (s, 3 H), 3.20- 3.25 (m, 2 H), 3.61-
3.71 (m, 2 H), 4.11- 4.19 (m, 2 H), 4.74 (s, 2 H), 6.53 (dd, J =
12.0, 2.0 Hz, 1 H), 6.83-6.86 (m, 1 H). CDCl3 540 [M + H]+ 10
6-[(1H-Tetrazol- 5-yl)methoxy]- 4-fluoro-1'-(8- methyl-4-oxo-
3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin- 2-yl)-1-(2,2,2-
trifluoroethyl) spiro[indolin- 3,4'-piperidin]- 2(1H)-one
##STR00034## 1.75-1.82 (m, 2 H), 2.00-2.10 (m, 2 H), 2.34-2.39 (m,
2 H), 3.04 (s, 3 H), 3.25- 3.30 (m, 2 H), 3.65- 3.74 (m, 2 H),
4.13- 4.21 (m, 2 H), 4.64 (q, J = 9.4 Hz, 2 H), 5.51-5.55 (m, 2 H),
6.73 (dd, J = 11.9, 2.0 Hz, 2 H), 6.92- 6.94 (m, 1 H). DMSO- d6 564
[M + H]+
TABLE-US-00004 TABLE 4 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 11 1-[4-Fluoro-1-
methyl-1'-(8- methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)-2- oxospiro[indolin- 3,4'-piperidin]-
6-yl]piperidin-4- carboxylic acid ##STR00035## 1.67-1.93 (m, 8 H),
2.02-2.12 (m, 2 H), 2.48-2.54 (m, 2 H), 2.55-2.64 (m, 1 H),
3.00-3.08 (m, 2 H), 3.09 (s, 3 H), 3.16 (s, 3 H), 3.28-3.33 (m, 2
H), 3.62-3.70 (m, 2 H), 3.92-4.01 (m, 2 H), 4.09-4.18 (m, 2 H),
6.11-6.18 (m, 2 H). CDCl3 525 [M + H]+ 12 1-[4-Fluoro-1-
methyl-1'-(8- methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)-2- oxospiro[indolin- 3,4'-piperidin]-
6-yl]azetidin-3- carboxylic acid ##STR00036## 1.76-1.90 (m, 4 H),
2.01-2.10 (m, 2 H), 2.48-2.53 (m, 2 H), 3.10 (s, 3 H), 3.17 (s, 3
H), 3.29-3.34 (m, 2 H), 3.59-3.68 (m, 1 H), 3.87-4.02 (m, 4 H),
4.07-4.16 (m, 4 H), 5.70-7.75 (m, 2 H). CDCl3 497 [M + H]+ 13
4-Chloro-1'-(4- hydroxy-8- methyl-6,7- dihydro-5H- pyrido[2,3-d]
pyrimidin-2-yl)- 1-methyl-7- (oxolan-3- yloxy)spiro [indol-3,4'-
piperidin]2-one ##STR00037## 1.55-1.61 (m, 2 H), 1.81-1.90 (m, 2
H), 2.15-2.29 (m, 2 H), 2.49 (t, J = 6.1 Hz, 2 H), 2.68-2.80 (m, 2
H), 3.08 (s, 3 H), 3.23-3.30 (m, 2 H), 3.46 (s, 3 H), 3.82-4.04 (m,
6 H), 4.17-4.29 (m, 2 H), 4.94-4.99 CDCl3 500 [M + H]+ (m, 1 H),
6.71 (d, J = 8.9 Hz, 1 H), 6.89 (d, J = 8.9 Hz, 1 H). 14
4-Chloro-1'-(4- hydroxy-8- methyl-6,7- dihydro-5H- pyrido[2,3-d]
pyrimidin-2- yl)-1-(2- hydroxy-2- methoxypropyl [indol-3,4'-
piperidin]-2-one ##STR00038## 1.23 (s, 6 H), 1.55- 1.66 (m, 2 H),
1.74-1.90 (m, 2 H), 2.49 (t, J = 6.3 Hz, 2 H), 2.73-2.87 (m, 2 H),
3.08 (s, 3 H), 3.22-3.36 (m, 2 H), 3.81-3.92 (m, 5 H), 4.13 (s, 2
H), 4.23-4.35 (m, 2 H), 6.82 (d, J = 8.9 Hz, 1 H), 6.95 (d, J = 8.9
Hz, 1 H). CDCl3 502 [M + H]+
TABLE-US-00005 TABLE 5 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 15 4-Fluoro-1'-(4-
hydroxy-8- methyl-6,7- dihydro-5H- pyrido[2,3-d] pyrimidin-2-
yl)-1-(2- hydroxy-2- methylpropyl) spiro[indol- 3,4'-piperidin]-
2-one ##STR00039## 1.29 (s, 6 H), 1.76- 1.91 (m, 4 H), 2.25- 2.42
(m, 2 H), 2.47 (br t, J = 6.1 Hz, 2 H), 3.08 (s, 3 H), 3.22-3.32
(m, 2 H), 3.73 (s, 2 H), 3.83- 3.99 (m, 2 H), 4.20- 4.33 (m, 1 H),
6.70- 6.80 (m, 1 H), 6.80- 6.87 (m, 1 H), 7.19- 7.25 (m, 1 H).
CDCl3 456 [M + H]+ 16 4-Fluoro-1'-(4- hydroxy-8- methyl-6,7-
dihydro-5H- pyrido[2,3-d] pyrimidin-2- yl)-6-(1- methylpyrazol-
4-yl)spiro[2- benzofuran- 3,4'-piperidin]- 1-one ##STR00040##
1.71-1.90 (m, 4 H), 2.34-2.55 (m, 4 H), 3.08 (s, 3 H), 3.19- 3.30
(m, 2 H), 3.38 (br t, J = 12.5 Hz, 2 H), 3.98 (s, 3 H), 4.68 (br d,
J = 13.2 Hz, 2 H), 7.42 (dd, J = 10.1, 1.2 Hz, 1 H), 7.69 (s, 1 H),
7.74-7.82 (m, 2 H). CDCl3 465 [M + H]+ 17 4-Fluoro-1- methyl-1'-
(8-methyl-4- oxo-3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin-
2-yl)-6-[4- (methylsulfonyl) piperazin-1- yl]spiro [indolin-3,4'-
piperidin]- ##STR00041## 1.77-1.87 (m, 4 H), 2.10-2.20 (m, 2 H),
2.39-2.50 (m, 2 H), 2.84 (s, 3 H), 3.07 (s, 3 H), 3.18 (s, 3 H),
3.20-3.28 (m, 2 H), 3.28-3.35 (m, 4 H), 3.36-3.43 (m, 4 H),
3.86-3.98 (m, 2 H), 4.09-4.22 (m, 2 H), 6.18-6.28 (m, 2 H), 10.55
CDCl3 560 [M + H]+ 2(1H)-one (br. s, 1 H). 18 Methyl 4-[4-
fluoro-1- methyl-1'-(8- methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)-2-oxospiro [indolin-3,4'- pyperidin]-6-
yl]piperazin-1- ##STR00042## 1.76-1.89 (m, 4 H), 2.10-2.21 (m, 2
H), 2.41-2.49 (m, 2 H), 3.06 (s, 3 H), 3.14- 3.21 (m, 7 H), 3.22-
3.29 (m, 2 H), 3.74 (s, 3 H), 3.57-3.68 (m, 4 H), 3.88-3.99 (m, 2
H), 4.10-4.21 (m, 2 H), 6.16-6.25 (m, 2 H), 10.59 (br. CDCl3 540 [M
+ H]+ carboxylate s, 1 H).
TABLE-US-00006 TABLE 6 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 19 6-(cis-2,6- Dimethyl-
morpholin- 4-yl)-4-fluoro- 1-methyl-1'- (8-methyl-4-
oxo-3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin- 2-yl)spiro
[indolin-3,4'- piperidin]- ##STR00043## 1.27 (d, J = 6.2 Hz, 6 H),
1.79-1.87 (m, 4 H), 2.11-2.20 (m, 2 H), 2.42-2.49 (m, 4 H), 3.07
(s, 3 H), 3.19 (s, 3 H), 3.23-3.27 (m, 2 H), 3.40-3.45 (m, 2 H),
3.73-3.82 (m, 2 H), 3.89-3.97 (m, 2 H), 4.07-4.15 (m, 2 H),
6.16-6.23 (m, 2 H). CDCl3 511 [M + H]+ 2(1H)-one 20 4-Fluoro-6-(4-
methoxy- piperidin-1-yl)- 1-methyl-1'- (8-methyl-4-
oxo-3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin- 2-yl)spiro
[indolin-3,4'- piperidin]- ##STR00044## 1.66-1.76 (m, 2 H),
1.79-1.87 (m, 4 H), 1.96-2.04 (m, 2 H), 2.10-2.20 (m, 2 H),
2.43-2.48 (m, 2 H), 2.96-3.04 (m, 2 H), 3.06 (s, 3 H), 3.17 (s, 3
H), 3.22-3.27 (m, 2 H), 3.36-3.44 (m, 4 H), 3.47-3.55 (m, 2 H),
3.89-3.98 CDCl3 511 [M + H]+ 2(1H)-one (m, 2 H), 4.09-4.17 (m, 2
H), 6.19-6.24 (m, 2 H). 21 1-[4-Fluoro-1- methyl-1'-(8-
methyl-4-oxo- 3,4,5,6,7,8- hexahydropyrido [2,3-d]pyrimidin-
2-yl)-2-oxospiro [indolin-3,4'- piperidin]-6-yl] piperidin-4-
carbonitrile ##STR00045## 1.79-1.87 (m, 4 H), 1.95-2.21 (m, 6 H),
2.44-2.49 (m, 2 H), 2.44-2.49 (m, 2 H), 2.80-2.88 (m, 1 H), 3.07
(s, 3 H), 3.13- 3.21 (m, 5 H), 3.22- 3.27 (m, 2 H), 3.40- 3.48 (m,
2 H), 3.88- 3.97 (m, 2 H), 4.09- 4.17 (m, 2 H), 6.18- CDCl3 506 [M
+ H]+ 6.25 (m, 2 H).
TABLE-US-00007 TABLE 7 Com- ESI pound 1H NMR MS Example Compound
name Structure .delta. ppm Solvent m/z 22 4-Fluoro-6-(4-
hydroxycyclo- hexyl)-1- methyl-1'-(8- methyl-4-oxo- 3,4,5,6,7,8-
hexahydro- pyrido[2,3-d] pyrimidin-2-yl) spiro[indolin-
3,4'-piperizin]- 2(1H)-one ##STR00046## 1.37-1.59 (m, 4 H),
1.78-1.87 (m, 4 H), 1.90-1.98 (m, 2 H), 2.04 (s, 1 H), 2.07- 2.15
(m, 2 H), 2.15- 2.28 (m, 2 H), 2.39- 2.55 (m, 3 H), 3.07 (s, 3 H),
3.19 (s, 3H), 3.21-3.26 (m, 2 H), 3.64-3.74 (m, 1 H), 3.88-3.98 (m,
2 H), 4.16-4.25 (m, CDCl3 495 [M + H]+ 2 H), 6.48 (d, J = 1.0 Hz, 1
H), 6.58 (dd, J = 11.0, 1.0 Hz, 1 H). 23 6-(cis-2,6- Dimethyl-
morpholin- 4-yl)-4- fluoro-1- methyl-1'-(4- oxo-3,4,5,6,7,8-
hexahydropyrido [2,3-d]pyrimidin- 2-yl)spiro [indolin-3,4'-
piperidin]- 2(1H)-one ##STR00047## 1.26 (s, 3 H), 1.29 (s, 3 H),
1.77-1.87 (m, 4 H), 2.07-2.24 (m, 2 H), 2.37-2.52 (m, 4 H), 3.19
(s, 3 H), 3.25-3.35 (m, 2 H), 3.37-3.50 (m, 2H), 3.72-4.00 (m, 4
H), 4.06-4.22 (m, 2 H), 4.64 (brs, 1 H), 6.12-6.27 (m, 2 H). CDCl3
497 [M + H]+ 24 6-(cis-2,6- Dimethyl- morpholin- 4-yl)-4- fluoro-1-
(2,2,2-trifluoro- ethyl)-1'-(4- oxo-3,4,5,6,7,8- hexahydropyrido
[2,3-d]pyrimidin- 2-yl)spiro [indolin-3,4'- piperidin]-
##STR00048## 1.26 (s, 3 H), 1.28 (s, 3 H), 1.77-1.87 (m, 4 H),
2.14-3.31 (m, 2 H), 2.37-2.53 (m, 4 H), 3.24-3.46 (m, 4 H),
3.69-3.93 (m, 4 H), 4.15-4.39 (m, 4 H), 4.65 (brs, 1 H), 6.16-6.34
(m, 2 H). CDCl3 565 [M + H]+ 2(1H)-one
Compound Example 101
(2R)-2-[5-(4-Ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-1H--
quinazolin-4-one
##STR00049##
[0345]<Step 1>
[0346] 2-amino-3-methylbenzamide (1.00 g) and
5-(4-ethoxyphenyl)-2H-1,2,3-triazol-4-carbaldehyde (1.74 g) were
suspended in ethanol (30 mL), and acetic acid (100 .mu.L) was
added. The suspension was heated to 150.degree. C. and reacted for
3 hours in a microwave reaction apparatus. The suspension was
cooled to room temperature, and stirred for 10 hours, and the
precipitated solid was taken by filtration. The solid was washed
with ethanol (3 mL) three times, and then dried by heating
(45.degree. C.) under reduced pressure to give
2-[5-(4-ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-
-1H-quinazolin-4-one (1.45 g) as a white solid.
[0347] .sup.1H-NMR (270M Hz, DMSO-d.sub.6) .delta.: 1.33 (t, J=6.9
Hz, 3H), 2.04 (s, 3H), 4.06 (q, J=6.9 Hz, 2H), 6.06 (s, 1H), 6.34
(brs, 1H), 6.69 (t, J=7.4 Hz, 1H), 7.01 (d, J=8.6 Hz, 2H), 7.15 (d,
J=6.9 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 8.23
(brs, 1H). MS (ESI) m/z: 350.36 [M+H].sup.+.
<Step 2>
[0348]
2-[5-(4-Ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-1-
H-quinazolin-4-one (136 mg) was optically resolved by
high-performance liquid chromatography (methanol/TFA=100/0.05) with
a chiral column (CHIRALPAC-IC, DAICEL) to give the title compound
(59.4 mg) as a white solid.
[0349] .sup.1H-NMR (270M Hz, DMSO-d.sub.6) .delta.: 1.33 (brt,
J=6.9 Hz, 3H), 2.03 (brs, 3H), 3.96-4.16 (m, 2H), 6.07 (brs, 1H),
6.32 (brs, 1H), 6.68 (brs, 1H), 7.01 (brd, J=7.3 Hz, 2H), 7.15
(brd, J=6.9 Hz, 1H), 7.56 (brd, J=6.9 Hz, 1H), 7.62-7.86 (m, 2H),
8.20 (brs, 1H), 14.84 (brs, 1H).
[0350] MS (ESI) m/z: 350.26 [M+H].sup.+.
[0351] [.alpha.].sub.D.sup.24=-148.degree. (C=0.1, MeOH)
[0352] The compounds of Compound Examples 102 to 108 and 113 were
prepared using the method of Compound Example 101 and methods based
thereon, and methods disclosed in literatures and methods based
thereon. Tables 8 to 10 below show the compounds of Compound
Examples 101 to 108 and 113. By X-ray diffraction performed under
the same conditions as described above, the compound prepared in
Compound Example 101 was confirmed to be a nicotinamide-type
compound which binds to the nicotinamide binding pocket of
tankyrase.
TABLE-US-00008 TABLE 8 Com- ESI pound .sup.1H NMR MS Example
Compound name Structure .delta. ppm Solvent m/z 101 (2R)-2-[5-(4-
Ethoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-8-methyl- 2,3-dihydro-1H-
quinazolin-4-one ##STR00050## 1.33 (br t, J = 6.9 Hz, 3 H), 2.03
(br s, 3 H), 3.96-4.16 (m, 2 H), 6.07 (br s, 1 H), 6.32 (br s, 1
H), 6.68 (br s, 1 H), 7.01 (br d, J = 7.3 Hz, 2 H), 7.15 (br d, J =
6.9 Hz, 1 H), 7.56 (br d, J = 6.9 Hz, 1 H), 7.62-7.86 (m, 2 H),
8.20 (br s, 1 H), 14.84 (br s, 1 H) DMSO- d6 350.26 [M + H]+ 102
2-[3-(3- Fluorophenyl)- 1H-pirazol-4-yl]- 1-methyl-2,3-
dihydroquina- zolin-4-one ##STR00051## 5.75 (br s, 1 H), 6.70 (br
d, J = 8.1 Hz, 1 H), 6.83 (br t, J = 7.3 IIz, 1 H), 7.05-7.61 (m, 6
H), 7.72 (br d, J = 7.6 Hz, 1 H), 8.48 (br s, 1 H), 12.63-13.46 (m,
1 H) DMSO- d6 323.28 [M + H]+ 103 2-[5-(4- Ethoxyphenyl)-
1H-pyrazol-4-yl]- 8-methyl-2,3- dihydro-1H- quinazolin-4-one
##STR00052## 1.33 (t, J = 6.9 Hz, 3 H), 2.07 (s, 3 H), 4.05 (q, J =
6.9 Hz, 2 H), 5.75 (s, 1 H), 6.02 (s, 1 H), 6.69 (t, J = 7.6 Hz, 1
H), 7.01 (br d, J = 8.6 Hz, 2 H), 7.16 (d, J = 6.6 Hz, 1 H),
7.51-7.62 (m, 3 H), 7.77 (br s, 1 H), 8.13 (s, 1 H), 12.99 (br s, 1
H) DMSO- d6 349.40 [M + H]+ 104 2-[5-(4- Methoxyphenyl)-
2H-1,2,3-triazol- 4-yl]-1-methyl- 2,3-dihydro- quinazolin-4-one
##STR00053## 3.80 (s, 3 H), 5.98 (d, J = 3.0 Hz, 1 H), 6.68 (d, J =
8.2 Hz, 1 H), 6.81 (t, J = 7.6 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2 H),
7.31-7.40 (m, 1 H), 7.61-7.75 (m, 3 H), 8.50 (d, J = 3.0 Hz, 1 H)
DMSO- d6 336.33 [M + H]+ 105 2-[5-(4- Methoxyphenyl)-
2H-1,2,3-triazol- 4-yl]-8-methyl- 2,3-dihydro-1H- quinazolin-4-one
##STR00054## 2.04 (s, 3 H), 3.79 (s, 3 H), 6.07 (s, 1 H), 6.35 (br
s, 1 H), 6.69 (t, J = 7.4 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 2 H), 7.15
(d, J = 7.3 Hz, 1 H), 7.56 (d, J = 6.9 Hz, 1 H), 7.74 (br d, J =
8.6 Hz, 2 H), 8.23 (br s, 1 H) DMSO- d6 336.23 [M + H]+
TABLE-US-00009 TABLE 9 Com- ESI pound .sup.1H NMR MS Example
Compound name Structure .delta. ppm Solvent m/z 106 11-[5-(4-
Methoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-1,10- diazatricyclo
[6.3.1.0.sup.4,12] dodeca- 4(12),5,7-trien- 9-one ##STR00055##
2.82-3.12 (m, 4 H), 3.77 (s, 3 H), 5.82 (s, 1 H), 6.75-6.89 (m, 1
H), 6.93-7.11 (m, 2 H), 7.27 (br d, J = 7.3 Hz, 1 H), 7.37 (br d, J
= 7.9 Hz, 1 H), 7.64-7.94 (m, 2 H), 8.16-8.27 (m, 1 H), 15.02 (br
s, 1 H) DMSO- d6 348.44 [M + H]+ 107 8-Methyl-2-[5-
(4-(trideuterio- methoxy) phenyl)-2H- 1,2,3-triazol-4- yl]-2,3-
dihydro-1H- quinazolin-4-one ##STR00056## 2.03 (s, 3 H), 6.07 (br
s, 1 H), 6.34 (br s, 1 H), 6.69 (t, J = 7.9 Hz, 1 H), 7.02 (br d, J
= 8.2 Hz, 2 H), 7.15 (br d, J = 7.3 Hz, 1 H), 7.56 (br d, J = 7.9
Hz, 1 H), 7.66-7.83 (m, 2 H), 8.22 (br s, 1 H), 14.86 (br s, 1 H)
DMSO- d6 339.28 [M + H]+ 108 2-[4-[4-(2,2- Difluoroethoxy)
phenyl]-2H- 1,2,3-triazol-5- yl]-8- methyl-2,3- dihydro-1H-
quinazolin-4-one ##STR00057## 2.03 (s, 3 H), 4.26- 4.45 (m, 2 H),
6.08 (br s, 1 H), 6.16- 6.79 (m, 3 H), 7.00- 7.23 (m, 3 H), 7.56
(br d, J = 7.3 Hz, 1 H), 7.64-7.90 (m, 2 H), 8.22 (br s, 1 H),
14.90 (br s, 1 H) DMSO- d6 386.27 [M + H]+
TABLE-US-00010 TABLE 10 Compound .sup.1H NMR ESI MS Example
Compound name Structure .delta. ppm Solvent m/z 113 2-[4-(4-
Methoxyphenyl)- 1H-pyrazol-3-yl]- 8-methyl-2,3- dihydro-1H-
quinazolin-4-one ##STR00058## 335.32 [M + H]+
Compound Example 109
2-[5-(4-Methoxyphenyl)-1H-pyrazol-4-yl]-1-methyl-2,3-dihydroquinazolin-4-o-
ne (CAS No. 1252133-21-3)
##STR00059##
[0354] The title compound was prepared using the method of Compound
Example 101.
Compound Example 110
4-(5-((E)-2-(4-(2-Chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,-
4-triazol-3-yl)ethenyl)-1,3,4-oxazol-2-yl]benzonitrile[4-(5-((E)-2-(4-(2-c-
hlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethe-
nyl)-1,3,4-oxadiazol-2-yl)benzonitrile; G007-LK]
[0355] The title compound was prepared in accordance with the
synthesis method disclosed in Patent Literature 3 etc. The compound
is an adenosine-type compound which binds to the adenosine binding
pocket of tankyrase.
Compound Example 111
N-(8-Quinolyl)-4-[[(3aR,7aS)-1,3-dioxo-4,7-methano-1,3,3a,4,7,7a-hexahydro-
-2H-isoindol]-2-yl]benzamide (IWR-1)
[0356] The title compound was prepared in accordance with the
synthesis method as disclosed in known literatures etc. The
compound is an adenosine-type compound which binds to the adenosine
binding pocket of tankyrase.
Compound Example 112
N-(Cyclopropylmethyl)-4-(4-methoxybenzoyl)-N-[(3,5,7,8-tetrahydro-4-oxo-4H-
-pyrano[4,3-d]pyrimidin-2-yl)methyl]-1-(piperidinacetamide)
(NVP-TNKS656)
[0357] The title compound was prepared in accordance with a
synthesis method as disclosed in Non Patent Literature 2 etc. The
compound is a dual-type compound which acts on both the
nicotinamide binding pocket and the adenosine binding pocket of
tankyrase.
(Test Example 1) Tankyrase Inhibitory Activity Test
[0358] The enzymatic activity of tankyrase 1 and the enzymatic
activity of tankyrase 2 were measured by the ELISA method based on
assessment of auto-poly(ADP-ribosyl)ation to evaluate the tankyrase
inhibitory activity of the compound prepared in each of Compound
Examples (test compound) (inhibitory activity against tankyrase 1
(TNKS1) and inhibitory activity against tankyrase 2 (TNKS2)).
First, Flag-tagged tankyrase 1 (1,024-1, 327aa, SAM+PARP) and
tankyrase 2 (613-1, 116aa, ANK5+SAM+PARP) were synthesized with a
cell-free protein expression system, and diluted with a Tris buffer
solution (50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 10% glycerol). 50
.mu.L of the diluted tankyrase 1 or tankyrase 2 was added to a
plate with an anti-FLAG M2 monoclonal antibody immobilized thereon
(Anti-FLAG High-Sensitivity M2-Coated Plate) (Sigma-Aldrich), and
the mixture was left to stand overnight at 4.degree. C. Thereafter,
the plate was washed four times with a PBS (PBST) buffer containing
0.1% TritonX-100.
[0359] Subsequently, the test compound diluted with an assay buffer
(50 mM Tris-HCl (pH 8.0), 4 mM MgCl.sub.2, 0.2 mM DTT) (DMSO was
used as a control) was added to each well of the plate, and the
mixture was left to stand at room temperature for 10 minutes.
Thereafter, a biotin-labeled NAD solution (225 .mu.M NAD, 25 .mu.M
6-Biotin-17-NAD (Travigen, Inc.)) was added and mixed as a donor
substrate, and the mixture was reacted at 30.degree. C. for 45
minutes. To blank wells was added distilled water instead of the
biotin-labeled NAD solution. After the reaction, the plate was
washed with a PBST buffer four times. Thereafter, HRP (horseradish
peroxidase)-labeled streptavidin (Travigen, Inc.) was diluted with
a PBS buffer by 1,000 times, and added to each well, and the
mixture was reacted at room temperature for 20 minutes. The plate
was washed with a PBST buffer four times, a chemiluminescent
substrate solution TACS-Sapphire (Travigen, Inc.) was then added to
each well, the mixture was reacted at room temperature for 20
minutes, and thechemiluminescence intensity was measured using a
chemiluminescence measuring apparatus.
[0360] The residual enzymatic activity in the presence of the test
compound was determined from the following expression. On the basis
of the residual enzymatic activity at each of multiple
concentrations of the test compound, the enzyme inhibitory activity
was calculated in terms of a 50%-inhibition concentration
(IC.sub.50 value) using data analysis software Origin (LightStone
Corp.). Residual activity (%)={(chemiluminescence intensity with
test compound added)-(chemiluminescence intensity of
blank)}/{(chemiluminescence intensity of
control)-(chemiluminescence intensity of blank))
[0361] For the TNKS1 (inhibitory activity against tankyrase 1) and
the TNKS2 (inhibitory activity against tankyrase 2) of each test
compound as measured through the above-mentioned method, a test
compound having an IC.sub.50 value of less than 0.02 .mu.M was
rated "A", a test compound having an IC.sub.50 value of 0.02 .mu.M
or more and less than 0.2 .mu.M was rated "B", a test compound
having an IC.sub.50 value of 0.2 .mu.M or more and less than 1
.mu.M was rated "C", and a test compounds having an IC.sub.50 value
of 1 .mu.M or more was rated "D". Tables 11 and 12 below show the
results.
(Test Example 2) Cell Proliferation Inhibitory Activity Test
[0362] The cell proliferation inhibitory activity of the compound,
which had been prepared in each of Compound Examples, against the
human colorectal cancer cell line COLO-320DM was evaluated by
Celltiter-Glo Luminescent Cell Viability Assay (Promega
Corporation; G7573). COLO-320DM cells were cultured in RPMI-1640
medium containing 2 mM glutamine (Wako Pure Chemical Industries,
Ltd; 189-02025) supplemented with 10% fetal bovine serum. The
cultured cells were washed with PBS, and then dissociated with
trypsin/EDTA, and a cell solution with 3.times.10.sup.4 cells/mL
was prepared.
[0363] Subsequently, the cell solution was seeded in a 96-well
microplate (Thermo/Nunc Company; 136101) in an amount of 70 .mu.L
per well, and cultured overnight under the condition of 37.degree.
C. and 5% COz. The next day, a test compound solution obtained by
diluting the test compound (DMSO solution) with a cell culture
medium (final concentration of DMSO was 1%) was added in an amount
of 10 .mu.L per well, and the mixture was reacted under the
condition of 37.degree. C. and 5% CO.sub.2 for 96 hours (a 1% DMSO
solution was used as a control). Thereafter, a Celltiter-Glo
Luminescent Cell Viability Assay reagent was added (Promega
Corporation; G7573) in an amount of 80 .mu.L per well, the mixture
was stirred with a shaker for 2 minutes while light was blocked
with an aluminum foil, and the mixture was incubated at room
temperature for 10 minutes.
[0364] Thereafter, a luminescence signal was measured with a
luminometer (Biotech Company; Synergy). The ratio of cell
proliferation in each compound addition group to cell proliferation
in a control group containing no test compound solution, where cell
proliferation in the control group is 100%, was determined, and the
value of a compound concentration necessary for suppressing the
amount of residual cells to 50% of that in the control (G150) was
calculated as the cell proliferation inhibitory activity. For the
COLO-320DM (cell proliferation inhibitory activity against
COLO-320DM) of each test compound as measured through the
above-mentioned method, a test compound having a G150 value of less
than 1 .mu.M was rated "A", a test compound having a G150 value of
1 .mu.M or more and less than 10 .mu.M was rated "B", a test
compound having a G150 value of 10 .mu.M or more was rated "C", and
an unevaluated test compound was designated as "NT". Tables 11 and
12 show the results along with the results of the tankyrase
inhibitory activity test.
TABLE-US-00011 TABLE 11 Compound Example TNKS1 TNKS2 COLO-320DM 1 A
A B 2 A A A 3 A A A 4 A A A 5 A A A 6 A A A 7 A A A 8 B B A 9 A A A
10 A A A 11 A A A 12 A A A 13 A A A 14 A A A 15 A A A 16 A A A 17 A
A A 18 B A A 19 A A A 20 B A A 21 B A A 22 A B A 23 A A A 24 A A
A
TABLE-US-00012 TABLE 12 Example TNKS1 TNKS2 COLO-320DM 101 A A A
102 A A B 103 A A B 104 A A B 105 A A A 106 A A B 107 A A A 108 A A
B 109 A A C 113 A B C
[0365] As shown in Tables 11 and 12, specified compounds prepared
in Compound Examples were confirmed to have sufficient tankyrase
inhibitory activity, and these compounds were confirmed to be
tankyrase inhibitory compounds having sufficient tankyrase
inhibitory activity.
(Test Example 3) MTT Assay
[0366] The ratio of residual cells after treatment of the human
colorectal cancer cell line DLD-1 with a combination of the
compound prepared in each Compound Example (test compound or
tankyrase inhibitory compound) and a microtubule inhibitory
compound was measured to evaluate the cell killing effect of the
combination on the human colorectal cancer cell line DLD-1. The
compounds of the test compound and the microtubule inhibitory
compound are as follows:
(Example 1): combination of the compound prepared in Compound
Example 1 and docetaxel, paclitaxel, vincristine or vinblastine
(Example 2): combination of the compound prepared in Compound
Example 5 and docetaxel, paclitaxel, vincristine or vinblastine
(Example 3): combination of the compound prepared in Compound
Example 19 and docetaxel, paclitaxel, vincristine or vinblastine
(Example 4): combination of the compound prepared in Compound
Example 101 and docetaxel, paclitaxel, vincristine or vinblastine
(Example 5): combination of the compound prepared in Compound
Example 110 (G007-LK) and docetaxel, paclitaxel, vincristine or
vinblastine (Example 6): combination of the compound prepared in
Compound Example 111 (IWR-1) and docetaxel, paclitaxel, vincristine
or vinblastine (Example 7): combination of the compound prepared in
Compound Example 112 (NVP-TNKS656) and docetaxel, paclitaxel,
vincristine or vinblastine
[0367] Taxotere (docetaxel hydrate, Sigma-Aldrich) was used as
docetaxel, Taxol (Sigma-Aldrich) was used as paclitaxel, Oncovin
(vincristine sulfate, Sigma-Aldrich) was used as vincristine, and
vinblastine sulfate (Wako Pure Chemical Industries, Ltd.) was used
as vinblastine.
[0368] First, the human colorectal cancer cell line DLD-1 was
suspended in RPMI1640 medium (hereinafter, medium) containing
inactivated 10% fetal bovine serum, and the cells were seeded in a
96-well microplate at 250 cells (75 .mu.L) per well. The cells were
subjected to stationary culture overnight in a CO.sub.2 incubator
at 37.degree. C., and a medium (25 .mu.L) containing a combination
of a test compound and a microtubule inhibitory compound in each of
above Examples was added in triplicate in such a manner that the
final concentrations of the test compound were 0, 1 and 3 .mu.M and
that the final concentrations of the microtubule inhibitory
compound were 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30 and 90 nM.
As a control, 25 .mu.L of a medium containing only dimethyl
sulfoxide (DMSO) which is a solvent was added. The cells were
cultured in a CO.sub.2 incubator at 37.degree. C. for 120 hours,
MTT ([3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium
bromide])/phosphate buffer physiological saline was then added in
such a manner that the final concentration was 0.5 mg/mL, and the
mixture was left to stand in a CO.sub.2 incubator at 37.degree. C.
for 4 hours. The medium was removed, and dimethyl sulfoxide was
added in an amount of 100 .mu.L per well. The mixture was stirred
at room temperature for 1 hour, and the absorbance of each well
(570 nm to 630 nm) was then measured with xMark Microplate
Spectrophotometer (Bio-Rad Laboratories, Inc.). The concentration
of the microtubule inhibitor at which the relative number of cells
compared to the number of cells without the microtubule inhibitory
compound is 50% was defined as an IC50 value for each concentration
of the test compound.
[0369] FIGS. 1A to 7D show relationships between the concentration
of each microtubule inhibitory compound and the relative number of
cells (IC50 curve) when the final concentrations of the test
compound are 0 .mu.M (single agent), 1 .mu.M and 3 .mu.M. Table 13
below shows IC50 values when the final concentrations of the test
compound are 0 .mu.M (single agent), 1 .mu.M and 3 .mu.M. In the
drawings, the IC50 curves of systems in which the final
concentrations of the test compound are 1 .mu.M and 3 .mu.M are
curves in which the IC50 value when the concentration of each
microtubule inhibitory compound such as docetaxel is 0 .mu.M (i.e.
there is no microtubule inhibitory compound) is calculated as 100%.
Hence, if the effect exhibited by a combination of each test
compound and each microtubule inhibitory compound is simply an
additive effect, the IC50 curves for the concentrations of
microtubule inhibitory compounds of systems in which the final
concentrations of the test compound are 1 .mu.M and 3 .mu.M each
coincide with the IC50 curve in which the final concentration of
the test compound is 0 .mu.M (single agent). In other words, since
the IC50 value of the microtubule inhibitor is smaller when the
final concentration of the test compound is 1 .mu.M or 3 .mu.M than
when the final concentration of the test compound is 0 .mu.M
(single agent), the cell killing effect of a combination of the
test compound and the microtubule inhibitory compound on the human
colorectal cancer cell line DLD-1 is not an additive effect but a
synergic effect of the compounds.
TABLE-US-00013 TABLE 13 Microtubule 0 .mu.M inhibitory (single
agent) 1 .mu.M 3 .mu.M Example compound IC50 (nM) 1 Docetaxel 2.987
2.084 1.006 Paclitaxel 9.385 5.507 3.557 Vincristine 7.639 3.103
2.140 Vinblastine 2.377 1.490 0.932 2 Docetaxel 2.987 1.802 0.799
Paclitaxel 9.385 5.041 2.405 Vincristine 7.639 2.651 1.263
Vinblastine 2.377 1.013 0.768 3 Docetaxel 2.987 1.372 0.778
Paclitaxel 9.385 5.050 2.797 Vincristine 7.639 2.711 0.978
Vinblastine 2.377 1.076 0.872 4 Docetaxel 2.696 2.196 0.849
Paclitaxel 7.967 5.247 1.506 Vincristine 7.439 2.804 0.732
Vinblastine 2.679 1.496 0.423 5 Docetaxel 2.987 1.650 0.891
Paclitaxel 9.385 6.201 3.484 Vincristine 7.639 2.591 2.081
Vinblastine 2.377 1.652 1.034 6 Docetaxel 3.180 2.019 1.954
Paclitaxel 15.222 6.355 5.886 Vincristine 13.655 6.293 4.703
Vinblastine 5.590 2.446 2.347 7 Docetaxel 3.180 2.135 1.925
Paclitaxel 15.222 7.270 6.209 Vincristine 13.655 6.731 5.322
Vinblastine 5.590 2.877 2.535
[0370] As shown in FIGS. 1A to 7D and Table 13, a combination of a
test compound and a microtubule inhibitory compound was confirmed
to exhibit a synergic cell killing effect on the human colorectal
cancer cell line DLD-1, and the combination according to the
present invention was confirmed to be useful as an anticancer agent
effective for treating and/or preventing proliferative diseases
such as a cancer.
[0371] When instead of the microtubule inhibitory compound, any of
other anticancer agents (temozolomide, melphalan, gemcitabine,
cytarabine (Ara-C), fluorouracil (5-FU), pemetrexed,
mercaptopurine, methotrexate, irinotecan (SN-38), etoposide
(VP-16), actinomycin D, daunorubicin, doxorubicin, bleomycin,
mitoxantrone, oxaliplatin, carboplatin and cisplatin) was used, and
the test compound prepared in Compound Example 5 was further added
thereto at a predetermined concentration, the cell survival rate
decreased to about 50%, where the cell survival rate was 100% when
only the anticancer agent was added at a predetermined
concentration. Thus, such a combination was confirmed to exhibit at
least an additive cell killing effect without cancelling each
other's action (Example 8 below shows the results of specific
examples).
[0372] That is, the present invention also relates to an anticancer
agent in which a tankyrase inhibitor containing at least one
compound of the formula (1) or (11) as an active ingredient is
combined with at least one anticancer agent selected from the group
consisting of an alkylating agent (e.g., temozolomide or
melphalan), an antimetabolite (e.g., gemcitabine, cytarabine
(Ara-C), fluorouracil (5-FU), pemetrexed, mercaptopurine or
methotrexate), a plant alkaloid (with the exclusion of microtubule
inhibitory compounds; e.g., irinotecan (SN-38) or etoposide
(VP-16)), a topoisomerase inhibitor (e.g., irinotecan (SN-38) or
etoposide (VP-16)), an agent serving as both a plant alkaloid and a
topoisomerase inhibitor (e.g., irinotecan (SN-38) or etoposide
(VP-16)), an anticancer antibiotic (e.g., actinomycin D,
daunorubicin, doxorubicin, bleomycin or mitoxantrone) and a
platinating agent (e.g., oxaliplatin, carboplatin or
cisplatin).
(Test Example 4) MTT Assay
[0373] The ratio of residual cells in treatment of the human
colorectal cancer cell line COLO-320DM with a combination of the
compound prepared in each Compound Example (test compound or
tankyrase inhibitory compound) and each of the anticancer agents
was measured to evaluate the cell killing effect of the combination
on the human colorectal cancer cell line COLO-320DM. The
combinations of test compounds and anticancer agents are as
follows.
(Example 8): combination of the compound prepared in Compound
Example 5 and temozolomide, melphalan, gemcitabine, cytarabine
(Ara-C), fluorouracil (5-FU), pemetrexed, mercaptopurine,
methotrexate, irinotecan (SN-38), etoposide (VP-16), actinomycin D,
daunorubicin, doxorubicin, bleomycin, mitoxantrone, oxaliplatin,
carboplatin or cisplatin (Example 9): combination of the compound
prepared in Compound Example 110 (G007-LK) and irinotecan (SN-38)
(Example 10): combination of the compound prepared in Compound
Example 11 and irinotecan (SN-38) (Example 11): combination of the
compound prepared in Compound Example 19 and irinotecan (SN-38)
(Example 12): combination of the compound prepared in Compound
Example 101 and irinotecan (SN-38) (Example 13): combination of the
compound prepared in Compound Example 1 and irinotecan (SN-38)
(Example 14): combination of the compound prepared in Compound
Example 113 and irinotecan (SN-38)
[0374] Commercially available compounds were used for temozolomide
(manufactured by Sigma-Aldric), melphalan (manufactured by
Signa-Aldrich), gemcitabine (Gemcitabine hydrochloride;
manufactured by Sigma-Aldric), cytarabine (Cytosine
.beta.-D-arabinofuranoside (Ara-C); manufactured by Sigma-Aldrich),
fluorouracil (5-Fluorouracil (5-FU); manufactured by
Sigma-Aldrich), pemetrexed (Pemetrexed disodium heptahydrate;
manufactured by Sigma-Aldrich), mercaptopurine (6-Mercaptopurine
monohydrate; manufactured by Sigma-Aldrich), methotrexate
(Methotrexate hydrate; manufactured by Sigma-Aldrich), irinotecan
(7-Ethyl-10-hydroxycamptothecin (SN-38); manufactured by
Sigma-Aldrich), etoposide (Etoposide (VP-16); manufactured by Enzo
Life Sciences, Inc.), actinomycin D (manufactured by nacalai
tesque), daunorubicin (Daunorubicin hydrochloride; Calbiochem),
doxorubicin (Doxorubicin hydrochloride; manufactured by
Sigma-Aldrich), bleomycin (Bleomycin sulfate; manufactured by Enzo
Life Sciences, Inc.), mitoxantrone (Mitoxantrone dihydrochloride;
manufactured by Sigma-Aldrich), oxaliplatin (manufactured by
Sigma-Aldrich), carboplatin (manufactured by Sigma-Aldrich) and
cisplatin (manufactured by Enzo Life Sciences, Inc.).
[0375] First, the human colorectal cancer cell line COLO-320DM was
suspended in RPMI1640 medium (hereinafter, medium) containing
inactivated 10% fetal bovine serum, and the cells were seeded in a
96-well microplate at 350 cells (75 .mu.L) per well. The cells were
subjected to stationary culture overnight in a CO.sub.2 incubator
at 37.degree. C. Thereafter, in Example 8, a medium (25 .mu.L)
containing a combination of the compound prepared in Compound
Example 5 and each of the anticancer agents was added in triplicate
in such a manner that the final concentrations of the test compound
(compound prepared in Compound Example 5) were 0 nM or 30 nM and
that the final concentrations of each anticancer agent were those
shown in Table 14. In Examples 9 to 14, a medium (25 .mu.L)
containing a combination of the compound prepared in each of
Compound Examples and each of the anticancer agents was added in
triplicate in such a manner that the final concentrations of the
test compound were 0 nM or those shown in FIGS. 9 to 14. As a
control, 25 .mu.L of a medium containing only dimethyl sulfoxide
(DMSO) which is a solvent was added. The cells were cultured in a
COz incubator at 37.degree. C. for 120 hours, MTT
([3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium
bromide])/phosphate buffer physiological saline was then added in
such a manner that the final concentration was 0.5 mg/mL, and the
mixture was left to stand in a CO.sub.2 incubator at 37.degree. C.
for 4 hours. The medium was removed, and dimethyl sulfoxide was
added in an amount of 100 .mu.L per well. The mixture was stirred
at room temperature for 1 hour, and the absorbance of each well
(570 nm to 630 nm) was then measured with xMark Microplate
Spectrophotometer (Bio-Rad Laboratories, Inc.). The concentration
of the anticancer agent at which the relative number of cells
compared to the number of cells without the anticancer agent is 50%
was defined as an IC50 value for each concentration of the test
compound.
[0376] FIGS. 8A to 8C and FIGS. 9 to 14 show relationships between
the concentration of each anticancer agent and the relative number
of cells (IC50 curve) when the final concentrations of the test
compound are 0 .mu.M (single agent) or specified
concentrations.
TABLE-US-00014 TABLE 14 Anticancer agent Treatment concentration
Temozolomide 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 .mu.M
Melphalan 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 .mu.M
Gemcitabine 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 nM
Cytarabine 0, 0.412, 1.23, 3.7, 11.1, 33.3, 100, 300, 900 nM
Fluorouracil 0, 0.00412, 0.0123, 0.037, 0.11, 0.33, 1, 3, 9 .mu.M
Pemetrexed 0, 0.412, 1.23, 3.7, 11.1, 33.3, 100, 300, 900 nM
Mercaptopurine 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 nM
Methotrexate 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 nM
Irinotecan 0, 0.0412, 0.123, 0.37, 1.11, 3.3 10, 30, 90 nM
Etoposide 0, 0.00412, 0.0123, 0.037, 0.11, 0.33, 1, 3, 9 .mu.M
Actinomycin D 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 nM
Daunorubicin 0, 0.412, 1.23, 3.7, 11.1, 33.3, 100, 300, 900 nM
Doxorubicin 0, 0.412, 1.23, 3.7, 11.1, 33.3, 100, 300, 900 nM
Bleomycin 0, 0.00412, 0.0123, 0.037, 0.11, 0.33, 1, 3, 9 .mu.M
Mitoxantrone 0, 0.412, 1.23, 3.7, 11.1, 33.3, 100, 300, 900 nM
Oxaliplatin 0, 0.00412, 0.0123, 0.037, 0.11, 0.33, 1, 3, 9 .mu.M
Carboplatin 0, 0.0412, 0.123, 0.37, 1.11, 3.3, 10, 30, 90 .mu.M
Cisplatin 0, 0.00412, 0.0123, 0.037, 0.11, 0.33, 1, 3, 9 .mu.M
[0377] As shown in FIGS. 8A to 8C, where the cell survival rate was
100% when only each anticancer agent was added in an amount of 30
nM, the cell survival rate decreased to about 50% when the test
compound prepared in Compound Example 5 was further added to the
anticancer agent in an amount of 30 nM. Thus, such a combination
was confirmed to exhibit at least an additive cell killing effect
without cancelling each other's action. As shown in FIGS. 9 to 14,
where the cell survival rate was 100% when only the anticancer
agent (irinotecan) was added in an amount of 30 nM, the cell
survival rate decreased to about 50% when the test compound
prepared in each of Compound Examples 110, 11, 19, 101, 1 and 113
was added in the concentration shown in each of the figures. Thus,
such a combination was confirmed to exhibit at least an additive
cell killing effect without cancelling each other's action.
INDUSTRIAL APPLICATION
[0378] As described above, the present invention can provide a
novel anticancer agent and a kit useful for treating and/or
preventing proliferative diseases such as a cancer.
* * * * *